The Experts below are selected from a list of 228 Experts worldwide ranked by ideXlab platform

David J. Kazierad - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and safety of the Glucagon Receptor Antagonist PF-06291874: A 12-week, randomized, dose-response study in patients with type 2 diabetes mellitus on background metformin therapy.
    Diabetes obesity & metabolism, 2018
    Co-Authors: David J. Kazierad, Arthur Bergman, Veena R. Somayaji, Kristin Chidsey, Roberto A. Calle
    Abstract:

    AIMS To conduct a dose-response assessment of the efficacy and safety of the Glucagon Receptor Antagonist PF-06291874 in adults with type 2 diabetes (T2DM) using stable doses of metformin. MATERIALS AND METHODS This randomized, double-blind, statin-stratified, placebo-controlled, 4-arm, parallel-group study was conducted in patients with T2DM who were receiving background metformin. After an 8-week, non-metformin oral antidiabetic agent washout period, 206 patients were randomized to placebo or PF-06291874 (30, 60 or 100 mg once daily) for 12 weeks. Glycosylated haemoglobin (HbA1c), fasting plasma glucose (FPG) and safety endpoints were assessed at baseline and post baseline. RESULTS Dose-dependent mean reductions from baseline in HbA1c for PF-06291874 ranged from -0.67% (-7.29 mmol/mol) to -0.93% (-10.13 mmol/mol), and for FPG from -16.6 to -33.3 mg/dL after 12 weeks of dosing. The incidence of hypoglycaemia was low and was similar between groups receiving PF-06291874 and placebo. Small, non-dose-dependent increases in LDL cholesterol (  2 mm Hg; diastolic BP > 1 mm Hg) were observed with PF-06291874. Modest non-dose-dependent median increases were observed across PF-06291874 groups at 12 weeks for alanine aminotransferase (range, 37.6-48.7 U/L vs placebo) and aspartate aminotransferase (range, 33.3-36.6 U/L vs placebo); these were not associated with bilirubin changes. Small increases were observed in body weight (< 0.5 kg) in each PF-06291874 group vs placebo. CONCLUSIONS In patients with T2DM, PF-06291874 significantly lowered HbA1c and glucose, was well tolerated and carried a low risk of hypoglycaemia. Small, non-dose-related increases in BP, lipids and hepatic transaminases were observed.

  • A 4-week study assessing the pharmacokinetics, pharmacodynamics, safety, and tolerability of the Glucagon Receptor Antagonist PF-06291874 administered as monotherapy in subjects with type 2 diabetes mellitus
    Diabetes research and clinical practice, 2017
    Co-Authors: Arthur Bergman, Beesan Tan, Veena R. Somayaji, Roberto A. Calle, David J. Kazierad
    Abstract:

    Abstract Aims The Glucagon Receptor Antagonist PF-06291874 has demonstrated robust glucose reductions in subjects with type 2 diabetes mellitus (T2DM) on background metformin. This study assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of PF-06291874 administered as monotherapy in subjects with T2DM. Methods After a ≥4-week antidiabetic therapy washout period, 172 subjects were randomized to placebo or PF-06291874 15, 35, 75, or 150 mg once daily for 28 days. Mean daily glucose (MDG), fasting plasma glucose (FPG), and predefined safety endpoints were assessed at baseline and day 28. Results Dose-dependent reductions (placebo-adjusted) from baseline in MDG ranged from 40.3 to 68.8 mg/dL and in FPG from 27.1 to 57.2 mg/dL after 28 days of dosing with PF-06291874. There were no significant changes in low-density lipoprotein cholesterol at doses ≤75 mg relative to placebo. Small, dose-dependent increases in alanine aminotransferase and aspartate aminotransferase were observed; however, the incidence of these values >3 × upper limit of normal was similar across doses. PF-06291874 exposures were consistent with previous studies and PF-06291874 was well tolerated, with minimal incidence of hypoglycemia. Conclusions PF-06291874 as monotherapy was well tolerated and produced robust reductions in plasma glucose following 4 weeks of dosing in subjects with T2DM.

  • Effects of multiple ascending doses of the Glucagon Receptor Antagonist PF-06291874 in patients with type 2 diabetes mellitus.
    Diabetes obesity & metabolism, 2016
    Co-Authors: David J. Kazierad, Arthur Bergman, Beesan Tan, Derek M. Erion, Veena R. Somayaji, D. S. Lee, Timothy P. Rolph
    Abstract:

    Aims To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of multiple ascending doses of the Glucagon Receptor Antagonist PF-06291874 in patients with type 2 diabetes mellitus (T2DM). Methods Patients were randomized to oral PF-06291874 or placebo on a background of either metformin (Part A, Cohorts 1–5: 5–150 mg once daily), or metformin and sulphonylurea (Part B, Cohorts 1–2: 15 or 30 mg once daily) for 14–28 days. A mixed-meal tolerance test (MMTT) was administered on days −1 (baseline), 14 and 28. Assessments were conducted with regard to pharmacokinetics, various pharmacodynamic variables, safety and tolerability. Circulating amino acid concentrations were also measured. Results PF-06291874 exposure was approximately dose-proportional with a half-life of ∼19.7–22.7 h. Day 14 fasting plasma glucose and mean daily glucose values were reduced from baseline in a dose-dependent manner, with placebo-corrected decreases of 34.3 and 42.4 mg/dl, respectively, at the 150 mg dose. After the MMTT, dose-dependent increases in Glucagon and total Glucagon-like peptide-1 (GLP-1) were observed, although no meaningful changes were noted in insulin, C-peptide or active GLP-1 levels. Small dose-dependent increases in LDL cholesterol were observed, along with reversible increases in serum aminotransferases that were largely within the laboratory reference range. An increase in circulating gluconeogenic amino acids was also observed on days 2 and 14. All dose levels of PF-06291874 were well tolerated. Conclusion PF-06291874 was well tolerated, has a pharmacokinetic profile suitable for once-daily dosing, and results in reductions in glucose with minimal risk of hypoglycaemia.

Mari R. Candelore - One of the best experts on this subject based on the ideXlab platform.

  • Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule Glucagon Receptor Antagonist.
    PloS one, 2012
    Co-Authors: Sajjad A. Qureshi, Mari R. Candelore, Xiaodong Yang, Edward J. Brady, Eric S. Muise, Guoqiang Jiang, Qing Dallas-yang
    Abstract:

    HyperGlucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the Glucagon Receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR Antagonist that blocks Glucagon binding to the human GCGR (hGCGR) and antagonizes Glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous Glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma Glucagon and Glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent Glucagon Receptor Antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.

  • Discovery of a novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes.
    Journal of medicinal chemistry, 2012
    Co-Authors: Yusheng Xiong, Sajjad A. Qureshi, Mari R. Candelore, Guoqiang Jiang, Qing Dallas-yang, Jian Guo, Rui Liang, Corey N. Miller, Peggy E. Mccann, Xinchun Tong
    Abstract:

    A potent, selective Glucagon Receptor Antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive Antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted Glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  • discovery of a novel Glucagon Receptor Antagonist n 4 1s 1 3 3 5 dichlorophenyl 5 6 methoxynaphthalen 2 yl 1h pyrazol 1 yl ethyl phenyl carbonyl β alanine mk 0893 for the treatment of type ii diabetes
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Yusheng Xiong, Sajjad A. Qureshi, Mari R. Candelore, Guoqiang Jiang, Jian Guo, Rui Liang, Corey N. Miller, Peggy E. Mccann, Qing Dallasyang, Xinchun Tong
    Abstract:

    A potent, selective Glucagon Receptor Antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive Antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted Glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  • Cloning and expression of canine Glucagon Receptor and its use to evaluate Glucagon Receptor Antagonists in vitro and in vivo
    European journal of pharmacology, 2006
    Co-Authors: Xiaodong Yang, Mari R. Candelore, William P. Feeney, Marla L. Yates, Don Hora, Ron M. Kim, Emma R. Parmee, Joel P. Berger, Bei B. Zhang, Sajjad A. Qureshi
    Abstract:

    Glucose homeostasis is maintained by the combined actions of insulin and Glucagon. HyperGlucagonemia and/or elevation of Glucagon/insulin ratio have been reported in diabetic patients and in animal models of diabetes. Therefore, antagonizing Glucagon Receptor function has long been considered a useful approach to lower hyperglycemia. Dogs serve as an excellent model for studying glycemic control and various aspects of Glucagon biology in vivo; however, the amino acid sequence of the dog Glucagon Receptor has not been reported. To better understand the pharmacology of the dog Glucagon Receptor and to characterize Glucagon Receptor Antagonists, we cloned a cDNA corresponding to the Glucagon Receptor from dog liver RNA. The dog Glucagon Receptor shares a significant (>75%) homology at both nucleotide and amino acid levels with the Glucagon Receptor from human, monkey, mouse, and rat. The protein is highly conserved among all species in areas corresponding to the 7 trans-membrane domains. However, it shows significant divergence at the carboxy terminus such that the Receptor from dog has the longest cytoplasmic tail among all species examined. When expressed in chinese hamster ovary cells, the dog Glucagon Receptor bound [125I]Glucagon with a K(d) of 477+/-106 pM. Glucagon stimulated the rise of intracellular cAMP levels in these cells with an EC(50) of 9.6+/-1.7 nM and such effects could be blocked by known peptidyl and non-peptidyl small molecule Antagonists. In addition we show that a small molecule Glucagon Receptor Antagonist with significant activity in cell based assays also blocked the ability of Glucagon to induce elevation in blood glucose in beagle dogs. These data demonstrate that the cloned cDNA encodes a functional dog Glucagon Receptor. The availability of the dog cDNA will facilitate the understanding of Glucagon pharmacology and aid in the characterization of novel Glucagon Antagonists that may serve as anti-hyperglycemic treatment for type 2 diabetes mellitus.

  • Direct observation (NMR) of the efficacy of Glucagon Receptor Antagonists in murine liver expressing the human Glucagon Receptor.
    Bioorganic & medicinal chemistry, 2005
    Co-Authors: Sheila M. Cohen, Mari R. Candelore, Laurie Tota, Victor D.-h. Ding, Corin O. Miller, Joseph L. Duffy, Brian A. Kirk, Gregory J. Kaczorowski, Jeffrey G. Werrmann, Michael Wright
    Abstract:

    Abstract The demonstration of pharmacodynamic efficacy of novel chemical entities represents a formidable challenge in the early exploration of synthetic lead classes. Here, we demonstrate a technique to validate the biological efficacy of novel Antagonists of the human Glucagon Receptor (hGCGR) in the surgically removed perfused liver prior to the optimization of the pharmacokinetic properties of the compounds. The technique involves the direct observation by 13C NMR of the biosynthesis of [13C]glycogen from [13C]pyruvate via the gluconeogenic pathway. The rapid breakdown of [13C]glycogen (glycogenolysis) following the addition of 50 pM exogenous Glucagon is then monitored in real time in the perfused liver by 13C NMR. The concentration-dependent inhibition of Glucagon-mediated glycogenolysis is demonstrated for both the peptidyl Glucagon Receptor Antagonist 1 and structurally diverse synthetic Antagonists 2–7. Perfused livers were obtained from a transgenic mouse strain that exclusively expresses the functional human Glucagon Receptor, conferring human relevance to the activity observed with Glucagon Receptor Antagonists. This technique does not provide adequate quantitative precision for the comparative ranking of active compounds, but does afford physiological evidence of efficacy in the early development of a chemical series of Antagonists.

Sajjad A. Qureshi - One of the best experts on this subject based on the ideXlab platform.

  • Anti-diabetic efficacy and impact on amino acid metabolism of GRA1, a novel small-molecule Glucagon Receptor Antagonist.
    PloS one, 2012
    Co-Authors: Sajjad A. Qureshi, Mari R. Candelore, Xiaodong Yang, Edward J. Brady, Eric S. Muise, Guoqiang Jiang, Qing Dallas-yang
    Abstract:

    HyperGlucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the Glucagon Receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR Antagonist that blocks Glucagon binding to the human GCGR (hGCGR) and antagonizes Glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous Glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma Glucagon and Glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent Glucagon Receptor Antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.

  • Discovery of a novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the treatment of type II diabetes.
    Journal of medicinal chemistry, 2012
    Co-Authors: Yusheng Xiong, Sajjad A. Qureshi, Mari R. Candelore, Guoqiang Jiang, Qing Dallas-yang, Jian Guo, Rui Liang, Corey N. Miller, Peggy E. Mccann, Xinchun Tong
    Abstract:

    A potent, selective Glucagon Receptor Antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive Antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted Glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  • discovery of a novel Glucagon Receptor Antagonist n 4 1s 1 3 3 5 dichlorophenyl 5 6 methoxynaphthalen 2 yl 1h pyrazol 1 yl ethyl phenyl carbonyl β alanine mk 0893 for the treatment of type ii diabetes
    Journal of Medicinal Chemistry, 2012
    Co-Authors: Yusheng Xiong, Sajjad A. Qureshi, Mari R. Candelore, Guoqiang Jiang, Jian Guo, Rui Liang, Corey N. Miller, Peggy E. Mccann, Qing Dallasyang, Xinchun Tong
    Abstract:

    A potent, selective Glucagon Receptor Antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive Antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for Glucagon Receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted Glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  • Cloning and expression of canine Glucagon Receptor and its use to evaluate Glucagon Receptor Antagonists in vitro and in vivo
    European journal of pharmacology, 2006
    Co-Authors: Xiaodong Yang, Mari R. Candelore, William P. Feeney, Marla L. Yates, Don Hora, Ron M. Kim, Emma R. Parmee, Joel P. Berger, Bei B. Zhang, Sajjad A. Qureshi
    Abstract:

    Glucose homeostasis is maintained by the combined actions of insulin and Glucagon. HyperGlucagonemia and/or elevation of Glucagon/insulin ratio have been reported in diabetic patients and in animal models of diabetes. Therefore, antagonizing Glucagon Receptor function has long been considered a useful approach to lower hyperglycemia. Dogs serve as an excellent model for studying glycemic control and various aspects of Glucagon biology in vivo; however, the amino acid sequence of the dog Glucagon Receptor has not been reported. To better understand the pharmacology of the dog Glucagon Receptor and to characterize Glucagon Receptor Antagonists, we cloned a cDNA corresponding to the Glucagon Receptor from dog liver RNA. The dog Glucagon Receptor shares a significant (>75%) homology at both nucleotide and amino acid levels with the Glucagon Receptor from human, monkey, mouse, and rat. The protein is highly conserved among all species in areas corresponding to the 7 trans-membrane domains. However, it shows significant divergence at the carboxy terminus such that the Receptor from dog has the longest cytoplasmic tail among all species examined. When expressed in chinese hamster ovary cells, the dog Glucagon Receptor bound [125I]Glucagon with a K(d) of 477+/-106 pM. Glucagon stimulated the rise of intracellular cAMP levels in these cells with an EC(50) of 9.6+/-1.7 nM and such effects could be blocked by known peptidyl and non-peptidyl small molecule Antagonists. In addition we show that a small molecule Glucagon Receptor Antagonist with significant activity in cell based assays also blocked the ability of Glucagon to induce elevation in blood glucose in beagle dogs. These data demonstrate that the cloned cDNA encodes a functional dog Glucagon Receptor. The availability of the dog cDNA will facilitate the understanding of Glucagon pharmacology and aid in the characterization of novel Glucagon Antagonists that may serve as anti-hyperglycemic treatment for type 2 diabetes mellitus.

  • A Novel Glucagon Receptor Antagonist Inhibits Glucagon-Mediated Biological Effects
    Diabetes, 2004
    Co-Authors: Sajjad A. Qureshi, Mari R. Candelore, Dan Xie, Xiaodong Yang, Laurie Tota, Victor D.-h. Ding, Alka Bansal, Corin O. Miller, Sheila M. Cohen
    Abstract:

    Glucagon maintains glucose homeostasis during the fasting state by promoting hepatic gluconeogenesis and glycogenolysis. HyperGlucagonemia and/or an elevated Glucagon-to-insulin ratio have been reported in diabetic patients and animals. Antagonizing the Glucagon Receptor is expected to result in reduced hepatic glucose overproduction, leading to overall glycemic control. Here we report the discovery and characterization of compound 1 (Cpd 1), a compound that inhibits binding of 125 I-labeled Glucagon to the human Glucagon Receptor with a half-maximal inhibitory concentration value of 181 ± 10 nmol/l. In CHO cells overexpressing the human Glucagon Receptor, Cpd 1 increased the half-maximal effect for Glucagon stimulation of adenylyl cyclase with a K DB of 81 ± 11 nmol/l. In addition, Cpd 1 blocked Glucagon-mediated glycogenolysis in primary human hepatocytes. In contrast, a structurally related analog (Cpd 2) was not effective in blocking Glucagon-mediated biological effects. Real-time measurement of glycogen synthesis and breakdown in perfused mouse liver showed that Cpd 1 is capable of blocking Glucagon-induced glycogenolysis in a dosage-dependent manner. Finally, when dosed in humanized mice, Cpd 1 blocked the rise of glucose levels observed after intraperitoneal administration of exogenous Glucagon. Taken together, these data suggest that Cpd 1 is a potent Glucagon Receptor Antagonist that has the capability to block the effects of Glucagon in vivo.

Eric G. Vajda - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and Safety of the Glucagon Receptor Antagonist RVT-1502 in Type 2 Diabetes Uncontrolled on Metformin Monotherapy: A 12-Week Dose-Ranging Study
    Diabetes care, 2019
    Co-Authors: Jeremy Pettus, David A. D'alessio, Juan P. Frias, Eric G. Vajda, James D. Pipkin, Julio Rosenstock, Gretchen Williamson, Miriam A. Zangmeister, Lin Zhi, Keith B. Marschke
    Abstract:

    OBJECTIVE Evaluate the safety and efficacy of RVT-1502, a novel oral Glucagon Receptor Antagonist, in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments. RESULTS Over 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P CONCLUSIONS Glucagon Receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849).

  • Glucagon Receptor Antagonist LGD-6972 Significantly Lowers HbA1c and Is Well Tolerated after 12-Week Treatment in Patients with Type 2 Diabetes Mellitus (T2DM) on Metformin
    Diabetes, 2018
    Co-Authors: Jeremy Pettus, David A. D'alessio, Juan P. Frias, Eric G. Vajda, James D. Pipkin, Gretchen Williamson, Miriam A. Zangmeister, Robert R. Henry, Lin Zhi
    Abstract:

    Inappropriately elevated levels of Glucagon are thought to contribute to increased hepatic glucose production in people with T2DM and exacerbate hyperglycemia. LGD-6972 is an orally bioavailable, small molecule Glucagon Receptor Antagonist. In a Phase 2, double-blind, placebo-controlled study, the safety and efficacy of LGD-6972 was evaluated in subjects with T2DM (HbA1c ≥7.0%-≤10.5%) on a stable dose of metformin. Patients were randomized to 5 mg (n = 43), 10 mg (n = 40), 15 mg (n = 42) LGD-6972, or placebo (n = 41) daily for 12 weeks. Mean HbA1c at baseline was 8.2% and did not differ among groups. A statistically significant decrease from baseline in HbA1c (p Disclosure J. Pettus: Advisory Panel; Self; Sanofi, Novo Nordisk Inc.. Consultant; Self; MannKind Corporation. Advisory Panel; Self; Insulet Corporation. Consultant; Self; Senseonics. E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. J. Pipkin: Employee; Self; Ligand Pharmaceuticals, Inc.. G. Williamson: None. M.A. Zangmeister: None. Y. Li: None. R.R. Henry: Consultant; Self; Abbott, Alere Inc., AstraZeneca. Research Support; Self; AstaReal. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Bristol-Myers Squibb Company. Advisory Panel; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Hitachi, Ltd.. Advisory Panel; Self; AstraZeneca. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Johnson & Johnson Services, Inc.. Research Support; Self; Lexicon Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Advisory Panel; Self; Merck & Co., Inc.. Consultant; Self; Merck & Co., Inc.. Research Support; Self; Viacyte, Inc.. Consultant; Self; Sanofi-Aventis. Advisory Panel; Self; Sanofi-Aventis. D. D9Alessio: Consultant; Self; Intarcia Therapeutics, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S. J.P. Frias: Research Support; Self; AbbVie Inc., Allergan, Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company. Consultant; Self; CeQur Corporation. Research Support; Self; Cirius Therapeutics, AstraZeneca, Calibra Medical, Elcelyx Therapeutics, Inc.. Consultant; Self; Elcelyx Therapeutics, Inc.. Research Support; Self; Eli Lilly and Company, Genentech, Inc., Ionis Pharmaceuticals, Inc., ICON plc., Janssen Pharmaceuticals, Inc.. Consultant; Self; Johnson & Johnson Diabetes Institute, LLC.. Research Support; Self; Lexicon Pharmaceuticals, Inc., Ligand Pharmaceuticals, Inc.. Consultant; Self; Ligand Pharmaceuticals, Inc.. Research Support; Self; Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Pfizer Inc., Sanofi. Consultant; Self; Sanofi. Speaker9s Bureau; Self; Sanofi. Research Support; Self; Theracos, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..

  • An Allosteric Glucagon Receptor Antagonist, LGD-6972, Displays Biased Receptor Signaling
    Diabetes, 2018
    Co-Authors: Eric G. Vajda, Lin Zhi, Keith B. Marschke
    Abstract:

    Glucagon Receptor Antagonists (GRA) are novel molecules in development for the treatment of type 1 and type 2 (T2DM) diabetes. LGD-6972 recently demonstrated robust efficacy in a 12-week, Phase 2 study in T2DM, reducing HbA1c by 1.2% from baseline, with a safety profile more favorable than other GRAs at this stage of development. LGD-6972 is structurally distinct from other small molecule GRAs, containing a sulphonic acid tail (SAT) rather than a carboxylic acid tail (CAT), potentially explaining this finding. We performed computational modeling of LGD-6972 bound to the Glucagon Receptor (GCGR) and compared it to x-ray crystallography data with Receptor bound MK-0893. The SAT of LGD-6972 creates a larger pocket between helix 6 and 7 in the GCGR transmembrane domain, and alters the orientation of helix 8. Activity of LGD-6972, MK-0893 and other SAT and CAT GRAs were examined in cellular models of Glucagon-stimulated cAMP accumulation, β-arrestin recruitment, and Receptor internalization. All tested GRAs were full (>95%) Antagonists of cAMP accumulation. CAT GRAs were full Antagonists of β-arrestin (≥96%) and Receptor internalization (≥94%). In contrast, SAT GRAs had reduced antagonism of β-arrestin (58-87%) and Receptor internalization (6-52%). The relative potency was also altered with greater potency for CAT GRAs on β-arrestin vs. cAMP, whereas the opposite was true for SAT GRAs. Furthermore, a LGD-6972 analog with a CAT and a MK-0893 analog with a SAT displayed CAT- and SAT-like activity, respectively, indicating a clear structure-activity relationship exists, with LGD-6972 displaying Receptor-biased signaling. To further investigate the potential differences among compounds, primary human hepatocytes were treated with Glucagon or Glucagon with MK-0893 or LGD-6972 and gene expression was analyzed by microarray. Broad differences between Glucagon and the GRAs were observed and future studies will investigate the effects of SAT and CAT compounds. Disclosure E.G. Vajda: Employee; Self; Ligand Pharmaceuticals, Inc. L. Zhi: Employee; Self; Ligand Pharmaceuticals, Inc. K. Marschke: Employee; Self; Ligand Pharmaceuticals, Inc..

  • Pharmacokinetics and pharmacodynamics of single and multiple doses of the Glucagon Receptor Antagonist LGD-6972 in healthy subjects and subjects with type 2 diabetes mellitus
    Diabetes obesity & metabolism, 2016
    Co-Authors: Eric G. Vajda, James D. Pipkin, Douglas Logan, Kenneth C. Lasseter, Danielle Armas, Diane J. Plotkin, Rong Zhou, David Klein, Xiaoxiong Wei
    Abstract:

    Aim To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple doses of a novel, oral Glucagon Receptor Antagonist, LGD-6972, in healthy subjects and subjects with type 2 diabetes (T2DM). Methods In the single ascending dose study, LGD-6972 (2 to 480 mg) was administered to healthy subjects (n = 48) and T2DM subjects (n = 8). In the multiple ascending dose study, healthy subjects (n = 12) received a dose of 15 mg LGD-6972 and T2DM subjects (n = 36) received doses of 5, 10 or 15 mg of LGD-6972 daily for 14 days. Results LGD-6972 had linear plasma pharmacokinetics consistent with once-daily dosing that was comparable in healthy and T2DM subjects. Dose-dependent decreases in fasting plasma glucose were observed in all groups with a maximum of 3.15 mmol/L (56.8 mg/dL) on day 14 in T2DM subjects. LGD-6972 also reduced plasma glucose in the postprandial state. Dose-dependent increases in fasting plasma Glucagon were observed, but Glucagon levels decreased and insulin levels increased after an oral glucose load in T2DM subjects. LGD-6972 was well tolerated at the doses tested without dose-related or clinically meaningful changes in clinical laboratory parameters. No subject experienced hypoglycemia. Conclusion Inhibition of Glucagon action by LGD-6972 was associated with decreases in glucose in both healthy and T2DM subjects, the magnitude of which was sufficient to predict improvement in glycemic control with longer treatment duration in T2DM patients. The safety and pharmacological profile of LGD-6972 after 14 days of dosing supports continued clinical development.

Christof M. Kazda - One of the best experts on this subject based on the ideXlab platform.

  • treatment with ly2409021 a Glucagon Receptor Antagonist increases liver fat in patients with type 2 diabetes
    Diabetes Obesity and Metabolism, 2017
    Co-Authors: Cristina B. Guzman, Xiaotian M. Zhang, Rong Liu, Arie Regev, Sudha S. Shankar, Parag Garhyan, Sreekumar G. Pillai, Christof M. Kazda, Naga Chalasani, Thomas Hardy
    Abstract:

    AIMS To evaluate whether treatment with LY2409021, a novel, selective Glucagon Receptor Antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D). METHODS Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c). RESULTS A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P < .001) and placebo (4.44%; P < .001), accompanied by significant elevations in alanine aminotransferase levels with LY2409021 vs sitagliptin (6.8 U/L; P = .039) and vs placebo (10.7 U/L; P < .001). No patients had concomitant elevations in bilirubin levels. LY2409021 treatment showed significant HbA1c reductions vs placebo (LS mean difference -0.77%; P < .001) but not sitagliptin (-0.20%; P = .383). Similar results were observed for fasting plasma glucose. LY2409021 was also associated with significant increases in systolic blood pressure vs sitagliptin (4.9 mm Hg; P = .030) and vs placebo (4.3 mm Hg; P = .029), as well as significant increases in body weight and total cholesterol. All effects of LY2409021 were reversible. CONCLUSION In this cohort of patients with T2D, chronic Glucagon Receptor antagonism with LY2409021 was associated with glucose-lowering but also demonstrated increases in hepatic fat, hepatic aminotransferases, and other adverse effects.

  • treatment with the Glucagon Receptor Antagonist ly2409021 increases ambulatory blood pressure in patients with type 2 diabetes
    Diabetes Obesity and Metabolism, 2017
    Co-Authors: Christof M. Kazda, Cristina B. Guzman, Parag Garhyan, Juan P. Frias, Irene Foga, Xuewei Cui, Cory R. Heilmann, Jihui Anne Yang, Thomas Hardy
    Abstract:

    Aims To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes. Materials and methods This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers. Results At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P  < .001). The 24-hour mean DBP and MAP also increased, with LSM differences of 1.37 mm Hg (95% CI: 0.66, 2.08; P  < .001) and 1.67 mm Hg (95% CI: 0.86, 2.47; P  < .001) vs placebo, respectively. At week 6, LY2409021 treatment reduced glycated hemoglobin (HbA1c) levels, with an LSM difference of −0.49% (−5.4 mmol/mol) (95% CI: −0.56%, −0.42% [−6.1, −4.6 mmol/mol]; P  < .001) vs placebo. Mean HbA1c at baseline was 7.3% (56 mmol/mol). Small but significant changes in serum lipid and aminotransferase levels were observed with LY2409021 treatment (all P  < .05 vs placebo). Conclusions Statistically significant increases in BP, MAP and serum lipid levels were observed with LY2409021 treatment at a dose that lowered HbA1c and glucose levels. These effects may limit the clinical utility of LY2409021 as a chronic treatment for type 2 diabetes.

  • Treatment with LY2409021, a Glucagon Receptor Antagonist, increases liver fat in patients with type 2 diabetes
    Diabetes obesity & metabolism, 2017
    Co-Authors: Cristina B. Guzman, Xiaotian M. Zhang, Rong Liu, Arie Regev, Sudha S. Shankar, Parag Garhyan, Sreekumar G. Pillai, Christof M. Kazda, Naga Chalasani, Thomas Hardy
    Abstract:

    AIMS To evaluate whether treatment with LY2409021, a novel, selective Glucagon Receptor Antagonist, is associated with changes in hepatic fat and other safety variables related to the benefit-risk profile for chronic use in patients with type 2 diabetes (T2D). METHODS Safety and efficacy were assessed in patients with T2D taking metformin and sulphonylurea who were randomized to LY2409021 20 mg (n = 65), placebo (n = 68), or sitagliptin 100 mg (n = 41). Key endpoints included change from baseline to month 6 in hepatic fat fraction (HFF), assessed by magnetic resonance imaging; hepatic aminotransferases; blood pressure; lipid profile; fasting plasma glucose; and glycated haemoglobin (HbA1c). RESULTS A significant increase in HFF was seen with LY2409021 vs sitagliptin (least squares [LS] mean difference 3.72%; P 

  • Treatment with the Glucagon Receptor Antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes.
    Diabetes obesity & metabolism, 2017
    Co-Authors: Christof M. Kazda, Cristina B. Guzman, Parag Garhyan, Juan P. Frias, Irene Foga, Xuewei Cui, Cory R. Heilmann, Jihui Anne Yang, Thomas Hardy
    Abstract:

    Aims To assess the effect of LY2409021 on systolic blood pressure (SBP) in patients with type 2 diabetes. Materials and methods This 6-week, randomized, crossover study evaluated the effects of once-daily administration of LY2409021 20 mg vs those of placebo on SBP, diastolic BP (DBP), and mean arterial pressure (MAP) using 24-hour ambulatory BP monitoring (ABPM) in 270 subjects treated with diet/exercise ± metformin. Other measures included changes in glycemic control, serum lipids, and hepatic safety markers. Results At 6 weeks of LY2409021 treatment, 24-hour mean SBP was increased, with a least squares mean (LSM) difference of 2.26 mm Hg vs placebo (95% CI: 1.11, 3.40; P  

  • Response to Comment on Kazda et al. Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies. Diabetes Care 2016;39:1241-1249.
    Diabetes care, 2016
    Co-Authors: Christof M. Kazda, Parag Garhyan, Ying Ding, Ronan P Kelly, Chunxue Shi, Chay Ngee Lim, David E. Watson, Andrew Lewin, William H. Landschulz
    Abstract:

    We appreciate the thoughtful comments raised by Agrawal and Gupta (1) on our recent article (2) on the efficacy and safety of the Glucagon Receptor Antagonist LY2409021 in patients with type 2 diabetes. We are pleased that they acknowledge that this study has provided further proof of efficacy of Glucagon antagonism as a treatment for type 2 diabetes with acceptable adverse effects at a dose of 30 mg (1). Agrawal and Gupta queried how we arrived at the unequal allocation to the treatment groups with the ratio of 1.5:2.1:1:1 (for 60 mg, 30 mg, 10 mg, and placebo, respectively). Our randomization was probability based and …