The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Ryan Greenwood - One of the best experts on this subject based on the ideXlab platform.
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Discovery of 4‑Amino‑N‑[(1S)‑1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H‑pyrrolo[2,3‑d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases
2016Co-Authors: Matt Addie, Peter Ballard, David Buttar, Claire Crafter, Gordon Currie, Barry R. Davies, Judit Debreczeni, Hannah Dry, Philippa Dudley, Ryan GreenwoodAbstract:Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model
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discovery of 4 amino n 1s 1 4 chlorophenyl 3 hydroxypropyl 1 7h pyrrolo 2 3 d pyrimidin 4 yl piperidine 4 carboxamide azd5363 an orally bioavailable potent inhibitor of akt kinases
Journal of Medicinal Chemistry, 2013Co-Authors: Matt Addie, Peter Ballard, David Buttar, Claire Crafter, Barry R. Davies, Judit Debreczeni, Hannah Dry, Philippa Dudley, Gordon S Currie, Ryan GreenwoodAbstract:Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.
Matt Addie - One of the best experts on this subject based on the ideXlab platform.
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Discovery of 4‑Amino‑N‑[(1S)‑1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H‑pyrrolo[2,3‑d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an Orally Bioavailable, Potent Inhibitor of Akt Kinases
2016Co-Authors: Matt Addie, Peter Ballard, David Buttar, Claire Crafter, Gordon Currie, Barry R. Davies, Judit Debreczeni, Hannah Dry, Philippa Dudley, Ryan GreenwoodAbstract:Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model
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discovery of 4 amino n 1s 1 4 chlorophenyl 3 hydroxypropyl 1 7h pyrrolo 2 3 d pyrimidin 4 yl piperidine 4 carboxamide azd5363 an orally bioavailable potent inhibitor of akt kinases
Journal of Medicinal Chemistry, 2013Co-Authors: Matt Addie, Peter Ballard, David Buttar, Claire Crafter, Barry R. Davies, Judit Debreczeni, Hannah Dry, Philippa Dudley, Gordon S Currie, Ryan GreenwoodAbstract:Wide-ranging exploration of analogues of an ATP-competitive pyrrolopyrimidine inhibitor of Akt led to the discovery of clinical candidate AZD5363, which showed increased potency, reduced hERG affinity, and higher selectivity against the closely related AGC kinase ROCK. This compound demonstrated good preclinical drug metabolism and pharmacokinetics (DMPK) properties and, after oral dosing, showed pharmacodynamic knockdown of phosphorylation of Akt and downstream biomarkers in vivo, and inhibition of tumor growth in a breast cancer xenograft model.
Mark Stidham - One of the best experts on this subject based on the ideXlab platform.
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pyrrolopyrimidine inhibitors of dna gyrase b gyrb and topoisomerase iv pare part i structure guided discovery and optimization of dual targeting agents with potent broad spectrum enzymatic activity
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: Leslie W Tari, Michael Trzoss, Daniel C Bensen, Zhiyong Chen, Thanh Lam, Junhu Zhang, Christopher J Creighton, Mark L Cunningham, Bryan P Kwan, Mark StidhamAbstract:The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity.
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Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE), Part II: development of inhibitors with broad spectrum, Gram-negative antibacterial activity.
Bioorganic & medicinal chemistry letters, 2012Co-Authors: Michael Trzoss, Daniel C Bensen, Zhiyong Chen, Thanh Lam, Junhu Zhang, Christopher J Creighton, Mark L Cunningham, Bryan P Kwan, Mark StidhamAbstract:The structurally related bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as prime candidates for the development of broad spectrum antibacterial agents. However, GyrB/ParE targeting antibacterials with spectrum that encompasses robust Gram-negative pathogens have not yet been reported. Using structure-based inhibitor design, we optimized a novel pyrrolopyrimidine inhibitor series with potent, dual targeting activity against GyrB and ParE. Compounds were discovered with broad antibacterial spectrum, including activity against Pseudomonas aeruginosa, Acinetobacter baumannii and Escherichia coli. Herein we describe the SAR of the pyrrolopyrimidine series as it relates to key structural and electronic features necessary for Gram-negative antibacterial activity.
Andrew D. Ferguson - One of the best experts on this subject based on the ideXlab platform.
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Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin-1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B-Cell Lymphoma
Journal of medicinal chemistry, 2017Co-Authors: James S. Scott, Sébastien L. Degorce, Rana Anjum, Janet D. Culshaw, Robert D. M. Davies, Nichola L. Davies, Keith Dillman, James E. Dowling, Lisa Drew, Andrew D. FergusonAbstract:Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model.
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Discovery and Optimization of Pyrrolopyrimidine Inhibitors of Interleukin‑1 Receptor Associated Kinase 4 (IRAK4) for the Treatment of Mutant MYD88L265P Diffuse Large B‑Cell Lymphoma
2017Co-Authors: James S. Scott, Sébastien L. Degorce, Rana Anjum, Janet D. Culshaw, Robert D. M. Davies, Nichola L. Davies, James E. Dowling, Lisa Drew, Keith S. Dillman, Andrew D. FergusonAbstract:Herein we report the optimization of a series of pyrrolopyrimidine inhibitors of interleukin-1 receptor associated kinase 4 (IRAK4) using X-ray crystal structures and structure based design to identify and optimize our scaffold. Compound 28 demonstrated a favorable physicochemical and kinase selectivity profile and was identified as a promising in vivo tool with which to explore the role of IRAK4 inhibition in the treatment of mutant MYD88L265P diffuse large B-cell lymphoma (DLBCL). Compound 28 was shown to be capable of demonstrating inhibition of NF-κB activation and growth of the ABC subtype of DLBCL cell lines in vitro at high concentrations but showed greater effects in combination with a BTK inhibitor at lower concentrations. In vivo, the combination of compound 28 and ibrutinib led to tumor regression in an ABC-DLBCL mouse model
George P Chrousos - One of the best experts on this subject based on the ideXlab platform.
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crhr1 receptor binding and lipophilicity of Pyrrolopyrimidines potential nonpeptide corticotropin releasing hormone type 1 receptor antagonists
Bioorganic & Medicinal Chemistry, 2002Co-Authors: Lingwei Hsin, Elizabeth L Webster, George P Chrousos, Xinrong Tian, Andrew Coop, Timothy M Caldwell, Arthur E Jacobson, Philip W Gold, Kamal E Habib, Alejandro R AyalaAbstract:Abstract A series of compounds related to N -butyl- N -ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3- d ]pyrimidin-4-yl]amine ( 1 , antalarmin, Fig. 1 ) have been prepared and evaluated for their CRHR 1 binding affinity as the initial step in the development of selective high affinity hydrophilic nonpeptide corticotropin-releasing hormone type 1 receptor (CRHR 1 ) antagonists. Calculated log P (Clog P) values were used to evaluate the rank order of hydrophilicity for these analogues. Introducing oxygenated functionalities (δ-hydroxy or bis-β-ethereal) into 1 gave more hydrophilic compounds, which had good affinity for the receptor. Introducing an amino group or shortening the alkyl side chain was detrimental to CRHR 1 affinity. The alcohol 4-[ethyl[2,5,6-trimethyl-7-(2,4,6-trimethylphenyl)pyrrolo[2,3- d ]pyrimidin-4-yl]amino]butan-1-ol ( 3 ), bearing a terminal hydroxyl group on an N -alkyl side-chain, showed the highest CRHR 1 binding affinity among these compounds ( K i =0.68 nM), and is one of the highest affinity CRHR 1 ligands known. Compounds 3 – 5 , and 8, which are likely to be less lipophilic than 1 , have high CRHR 1 affinity and may be valuable probes to further study the CRH system.
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chronic administration of the non peptide crh type 1 receptor antagonist antalarmin does not blunt hypothalamic pituitary adrenal axis responses to acute immobilization stress
Life Sciences, 1999Co-Authors: Mali Wong, Elizabeth L Webster, George P Chrousos, Helen Spokes, Phan Phu, Monika Ehrhartbornstein, Stefan R Bornstein, Chulsoo Park, Julio LicinioAbstract:Antalarmin is a pyrrolopyrimidine compound that antagonizes corticotropin-releasing hormone (CRH) type 1 receptors (CRHR1). In order to assess the effects of antalarmin treatment on hypothalamic-pituitary-adrenal (HPA) function we measured the plasma concentrations of adrenocorticotropic hormone (ACTH) and corticosterone in animals treated with either antalarmin or vehicle for 1 week or for 8 weeks. We found that antalarmin treatment for 1 week did not affect basal concentrations of ACTH or corticosterone. In contrast, treatment for 8 weeks significantly lowered basal ACTH and corticosterone concentrations and also significantly decreased the basal corticosterone to ACTH ratio, indicating decreased basal adrenocortical responsiveness to ACTH. However, immobilization stress resulted in ACTH and corticosterone concentrations that were the same in animals treated with vehicle or antalarmin for either 1 or 8 weeks. We conclude that even though 8-week antagonism of CRHR1 by the non-peptide antalarmin blunts basal concentrations of ACTH and corticosterone, and affects the adrenal responsiveness to ACTH, it does not blunt the HPA response to acute stress, and it does not appear to cause stress-induced adrenal insufficiency.
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in vivo and in vitro characterization of antalarmin a nonpeptide corticotropin releasing hormone crh receptor antagonist suppression of pituitary acth release and peripheral inflammation
Endocrinology, 1996Co-Authors: Elizabeth L Webster, D B Lewis, David J Torpy, E K Zachman, George P ChrousosAbstract:Corticotropin-releasing hormone (CRH) secreted from the hypothalamus is the major regulator of pituitary ACTH release and consequent glucocorticoid secretion. CRH secreted in the periphery also acts as a proinflammatory modulator. CRH receptors (CRH-R1, R2alpha, R2beta) exhibit a specific tissue distribution. Antalarmin, a novel pyrrolopyrimidine compound, displaced 12SI-oCRH binding in rat pituitary, frontal cortex and cerebellum, but not heart, consistent with antagonism at the CRHR1 receptor. In vivo antalarmnin (20 mg/kg body wt.) significantly inhibited CRH-stimulated ACTH release and carageenin-induced subcutaneous inflammation in rats. Antalarmin, or its analogs, hold therapeutic promise in disorders with putative CRH hypersecretion, such as melancholic depression and inflammatory disorders.
