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Christopher H. Fotsch - One of the best experts on this subject based on the ideXlab platform.
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Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
Journal of medicinal chemistry, 2015Co-Authors: Nuria A. Tamayo, Fang-tsao Hong, Mark H. Norman, Michael D. Bartberger, Longbin Liu, Nobuko Nishimura, Kevin Yang, Seifu Tadesse, Christopher H. FotschAbstract:The Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
Journal of medicinal chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 4 exploration of a novel binding pocket
Journal of Medicinal Chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N′-arylpiperazine Series
Journal of medicinal chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 3 structure activity relationships within the aryl carbinol region of the n arylsulfonamido n arylpiperazine series
Journal of Medicinal Chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
Dolores Corella - One of the best experts on this subject based on the ideXlab platform.
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relevant associations of the Glucokinase Regulatory Protein Glucokinase gene variation with tag concentrations in a high cardiovascular risk population modulation by the mediterranean diet
British Journal of Nutrition, 2013Co-Authors: Mercedes Sotosprieto, Marisa Guillen, Jose V Sorli, Olga Portoles, Patricia Guillemsaiz, Jose I Gonzalez, Dolores CorellaAbstract:The SNP rs1260326 (P446L) and rs1799884 (-30G>A) for the Glucokinase Regulatory Protein (GCKR) and Glucokinase (GCK) genes, respectively, have been associated with opposing effects on TAG and glucose concentrations. However, their genetic modulation by diet (dietary patterns or foods) remains to be investigated. We studied 945 high-cardiovascular risk subjects aged 67 (sd 6) years who participated in the PREvencion con DIeta MEDiterranea-Valencia Study. Demographic, clinical, biochemical and genetic data were obtained. Adherence to the Mediterranean diet (MD) and food intake were measured by validated questionnaires. Carriers of the L allele of GKCR had significantly higher TAG concentrations (PP: 1.34 (SD 0.05) mmol/l v. PL+LL: 1.54 (SD 0.03) mmol/l; P= 0.014) and LL carriers had lower glucose concentrations (PL+PP: 6.85 (SD 0.08) mmol/l v. LL: 6.40 (SD 0.16) mmol/l; P= 0.032) after multivariate adjustment. Conversely, homozygous subjects for the variant allele (A) in the GCK gene had significantly lower TAG (GG+GA: 1.48 (SD 0.03) mmol/l v. AA: 1.17 (SD 0.18) mmol/l; P= 0.033) and a higher risk of diabetes (OR 3.3, 95 % CI 1.2, 9.2). Combined effects for both SNP increased TAG concentrations by 37 % (P= 0.033). Adherence to the MD modulated the effects of GCKR polymorphism on TAG: subjects with genetic risk had lower TAG (L-allele carriers; PP: 1.48 (SD 0.14) mmol/l v. PL+LL: 1.51 (SD 0.08) mmol/l; P= 0.917) compared with those with a higher adherence. Analysis of the joint effects of the GCKR and individual food items identified significant associations (olive oil (P= 0.035), vegetables (P= 0.012), red meat (P= 0.017), butter (P= 0.039), sweetened carbonated beverages (P= 0.036) and nuts (P= 0.038)). In conclusion, we found that rs1260326 (GCKR) is significantly associated with higher TAG concentrations, but is modulated by adherence to the MD.
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Relevant associations of the Glucokinase Regulatory Protein/Glucokinase gene variation with TAG concentrations in a high-cardiovascular risk population: modulation by the Mediterranean diet
The British journal of nutrition, 2012Co-Authors: Mercedes Sotos-prieto, Marisa Guillen, Jose V Sorli, Olga Portoles, Jose I Gonzalez, Patricia Guillem-saiz, Dolores CorellaAbstract:The SNP rs1260326 (P446L) and rs1799884 (-30G>A) for the Glucokinase Regulatory Protein (GCKR) and Glucokinase (GCK) genes, respectively, have been associated with opposing effects on TAG and glucose concentrations. However, their genetic modulation by diet (dietary patterns or foods) remains to be investigated. We studied 945 high-cardiovascular risk subjects aged 67 (sd 6) years who participated in the PREvencion con DIeta MEDiterranea-Valencia Study. Demographic, clinical, biochemical and genetic data were obtained. Adherence to the Mediterranean diet (MD) and food intake were measured by validated questionnaires. Carriers of the L allele of GKCR had significantly higher TAG concentrations (PP: 1.34 (SD 0.05) mmol/l v. PL+LL: 1.54 (SD 0.03) mmol/l; P= 0.014) and LL carriers had lower glucose concentrations (PL+PP: 6.85 (SD 0.08) mmol/l v. LL: 6.40 (SD 0.16) mmol/l; P= 0.032) after multivariate adjustment. Conversely, homozygous subjects for the variant allele (A) in the GCK gene had significantly lower TAG (GG+GA: 1.48 (SD 0.03) mmol/l v. AA: 1.17 (SD 0.18) mmol/l; P= 0.033) and a higher risk of diabetes (OR 3.3, 95 % CI 1.2, 9.2). Combined effects for both SNP increased TAG concentrations by 37 % (P= 0.033). Adherence to the MD modulated the effects of GCKR polymorphism on TAG: subjects with genetic risk had lower TAG (L-allele carriers; PP: 1.48 (SD 0.14) mmol/l v. PL+LL: 1.51 (SD 0.08) mmol/l; P= 0.917) compared with those with a higher adherence. Analysis of the joint effects of the GCKR and individual food items identified significant associations (olive oil (P= 0.035), vegetables (P= 0.012), red meat (P= 0.017), butter (P= 0.039), sweetened carbonated beverages (P= 0.036) and nuts (P= 0.038)). In conclusion, we found that rs1260326 (GCKR) is significantly associated with higher TAG concentrations, but is modulated by adherence to the MD.
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association between Glucokinase Regulatory Protein gckr and apolipoProtein a5 apoa5 gene polymorphisms and triacylglycerol concentrations in fasting postprandial and fenofibrate treated states
The American Journal of Clinical Nutrition, 2009Co-Authors: Pablo Perezmartinez, Dolores Corella, Jian Shen, Donna K. Arnett, Nikos Yiannakouris, Katherine L. Tucker, Michael Y. Tsai, Syong E Tai, Marju Orhomelander, Robert J. StrakaAbstract:Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoProtein A5 (APOA5) and Glucokinase Regulatory Protein (GCKR) genes has been associated with fasting plasma triacylglycerol. Objective: We investigated the combined effects of the GCKR rs780094C→T, APOA5 −1131T→C, and APOA5 56C→G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. Design: We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7730 men and women) and 2 intervention studies in US whites (n = 1061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). Results: Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend <0.001). Conclusions: SNPs in GCKR and APOA5 have an additive effect on both fasting and postprandial triacylglycerol and contribute to the interindividual variability in response to fenofibrate treatment.
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Association between Glucokinase Regulatory Protein (GCKR) and apolipoProtein A5 (APOA5) gene polymorphisms and triacylglycerol concentrations in fasting, postprandial, and fenofibrate-treated states
The American journal of clinical nutrition, 2008Co-Authors: Pablo Pérez-martinez, Dolores Corella, Jian Shen, Donna K. Arnett, Nikos Yiannakouris, E Syong Tai, Marju Orho-melander, Katherine L. Tucker, Michael Y. Tsai, Robert J. StrakaAbstract:Background: Hypertriglyceridemia is a risk factor for cardiovascular disease. Variation in the apolipoProtein A5 (APOA5) and Glucokinase Regulatory Protein (GCKR) genes has been associated with fasting plasma triacylglycerol. Objective: We investigated the combined effects of the GCKR rs780094C→T, APOA5 −1131T→C, and APOA5 56C→G single nucleotide polymorphisms (SNPs) on fasting triacylglycerol in several independent populations and the response to a high-fat meal and fenofibrate interventions. Design: We used a cross-sectional design to investigate the association with fasting triacylglycerol in 8 populations from America, Asia, and Europe (n = 7730 men and women) and 2 intervention studies in US whites (n = 1061) to examine postprandial triacylglycerol after a high-fat meal and the response to fenofibrate. We defined 3 combined genotype groups: 1) protective (homozygous for the wild-type allele for all 3 SNPs); 2) intermediate (any mixed genotype not included in groups 1 and 3); and 3) risk (carriers of the variant alleles at both genes). Results: Subjects within the risk group had significantly higher fasting triacylglycerol and a higher prevalence of hypertriglyceridemia than did subjects in the protective group across all populations. Moreover, subjects in the risk group had a greater postprandial triacylglycerol response to a high-fat meal and greater fenofibrate-induced reduction of fasting triacylglycerol than did the other groups, especially among persons with hypertriglyceridemia. Subjects with the intermediate genotype had intermediate values (P for trend
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common missense variant in the Glucokinase Regulatory Protein gene is associated with increased plasma triglyceride and c reactive Protein but lower fasting glucose concentrations
Diabetes, 2008Co-Authors: Marju Orhomelander, Dolores Corella, Pablo Perezmartinez, Olle Melander, Candace Guiducci, Charlotta Roos, Ryan Tewhey, Mark J Rieder, Jennifer L HallAbstract:Abstract OBJECTIVE Using the genome-wide-association approach, we recently identified the Glucokinase Regulatory Protein gene ( GCKR , rs780094) region as a novel quantitative trait locus for plasma triglyceride concentration in Europeans. Here, we sought to study the association of GCKR variants with metabolic phenotypes including measures of glucose homeostasis, to evaluate the GCKR locus in samples of non-European ancestry, and to fine-map across the associated genomic interval. RESEARCH DESIGN AND METHODS We performed association studies in 12 independent cohorts comprising a total of >45,000 individuals representing several ancestral groups (whites from Northern and Southern Europe, whites from the United States, African Americans from the United States, Hispanics of Caribbean origin, and Chinese, Malays and Asian Indians from Singapore). We conducted genetic fine-mapping across the ∼417 kilobase region of linkage disequilibrium spanning GCKR and 16 other genes on chromosome 2p23 by imputing untyped HapMap SNPs and genotyping 104 SNPs across the associated genomic interval.. RESULTS We provide comprehensive evidence that GCKR rs780094 is associated with opposite effects on fasting plasma triglyceride (p meta =3x10 -56 ) and glucose (p meta =1x10 -13 ) concentrations. In addition, we confirmed recent reports that the same SNP is associated with C-reative Protein level (p=5x10 -5 ). Both fine mapping approaches revealed a common missense GCKR variant (rs1260326, Pro446Leu, 34% frequency, r 2 =0.93 with rs780094) as the strongest association signal in the region. CONCLUSIONS- These findings point to a molecular mechanism in humans by which higher triglycerides and C-reactive Protein can be coupled with lower plasma glucose concentrations and position GCKR in central pathways regulating both hepatic triglyceride and glucose metabolism.
Mark H. Norman - One of the best experts on this subject based on the ideXlab platform.
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Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
Journal of medicinal chemistry, 2015Co-Authors: Nuria A. Tamayo, Fang-tsao Hong, Mark H. Norman, Michael D. Bartberger, Longbin Liu, Nobuko Nishimura, Kevin Yang, Seifu Tadesse, Christopher H. FotschAbstract:The Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis
2015Co-Authors: Nuria A. Tamayo, Fang-tsao Hong, Mark H. Norman, Michael D. Bartberger, Longbin Liu, Nobuko Nishimura, Seifu Tadesse, Kevin C. Yang, Christopher FotschAbstract:The Glucokinase–Glucokinase Regulatory Protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
Journal of medicinal chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 4 exploration of a novel binding pocket
Journal of Medicinal Chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N′-arylpiperazine Series
Journal of medicinal chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
Michael D. Bartberger - One of the best experts on this subject based on the ideXlab platform.
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Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis.
Journal of medicinal chemistry, 2015Co-Authors: Nuria A. Tamayo, Fang-tsao Hong, Mark H. Norman, Michael D. Bartberger, Longbin Liu, Nobuko Nishimura, Kevin Yang, Seifu Tadesse, Christopher H. FotschAbstract:The Glucokinase-Glucokinase Regulatory Protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure-activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK.
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis
2015Co-Authors: Nuria A. Tamayo, Fang-tsao Hong, Mark H. Norman, Michael D. Bartberger, Longbin Liu, Nobuko Nishimura, Seifu Tadesse, Kevin C. Yang, Christopher FotschAbstract:The Glucokinase–Glucokinase Regulatory Protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone 93, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
Journal of medicinal chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 4 exploration of a novel binding pocket
Journal of Medicinal Chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N′-arylpiperazine Series
Journal of medicinal chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
Rod Cupples - One of the best experts on this subject based on the ideXlab platform.
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket
Journal of medicinal chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 4 exploration of a novel binding pocket
Journal of Medicinal Chemistry, 2014Co-Authors: Fang-tsao Hong, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Christopher H. Fotsch, Steven R. Jordan, David LloydAbstract:Structure–activity relationship investigations conducted at the 5-position of the N-pyridine ring of a series of N-arylsulfonyl-N′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (51) that was a potent disruptor of the Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound 51 bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the Protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound 51 was potent in both biochemical and cellular assays (IC50 = 0.005 μM and EC50 = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to db/db mice (100 mg/kg, po), compound 51 demonstrated a robust pharmacodynamic effect and significantly...
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Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 3. Structure–Activity Relationships within the Aryl Carbinol Region of the N-Arylsulfonamido-N′-arylpiperazine Series
Journal of medicinal chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
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small molecule disruptors of the Glucokinase Glucokinase Regulatory Protein interaction 3 structure activity relationships within the aryl carbinol region of the n arylsulfonamido n arylpiperazine series
Journal of Medicinal Chemistry, 2014Co-Authors: Nobuko Nishimura, Rod Cupples, Mark H. Norman, Kate Ashton, Michael D. Bartberger, Jie Chen, Samer Chmait, Longbin Liu, Kevin Yang, Christopher H. FotschAbstract:We have recently reported a novel approach to increase cytosolic Glucokinase (GK) levels through the binding of a small molecule to its endogenous inhibitor, Glucokinase Regulatory Protein (GKRP). These initial investigations culminated in the identification of 2-(4-((2S)-4-((6-amino-3-pyridinyl)sulfonyl)-2-(1-propyn-1-yl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (1, AMG-3969), a compound that effectively enhanced GK translocation and reduced blood glucose levels in diabetic animals. Herein we report the results of our expanded SAR investigations that focused on modifications to the aryl carbinol group of this series. Guided by the X-ray cocrystal structure of compound 1 bound to hGKRP, we identified several potent GK–GKRP disruptors bearing a diverse set of functionalities in the aryl carbinol region. Among them, sulfoximine and pyridinyl derivatives 24 and 29 possessed excellent potency as well as favorable PK properties. When dosed orally in db/db mice, both compounds significantly lower...
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Small molecule disruptors of the Glucokinase-Glucokinase Regulatory Protein interaction: 1. Discovery of a novel tool compound for in vivo proof-of-concept.
Journal of medicinal chemistry, 2014Co-Authors: Kate Ashton, Rod Cupples, Michelle Chen, Kui Chen, Jie Chen, Samer Chmait, Kristin L. Andrews, Marion C. Bryan, Michael Croghan, Christopher H. FotschAbstract:Small molecule activators of Glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of Glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, Glucokinase Regulatory Protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally, hypoglycemia was not observed in either the hyperglycemic or normal rats.