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Discovery of LY3104607: A Potent and Selective G Protein-Coupled Receptor 40 (GPR40) Agonist with Optimized Pharmacokinetic Properties to Support Once Daily Oral Treatment in Patients with Type 2 Diabetes Mellitus
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01411 Chafiq Hamdouchi 1 , Pranab Maiti 2 , Alan M. Warshawsky 1 , Amy C. DeBaillie 1 , Keith A. Otto 1 , Kelly L. Wilbur 1 , Steven D. Kahl 1 , Anjana Patel Lewis 1 , Guemalli R. Cardona 1 , Richard W. Zink 1 , Keyue Chen 1 , Siddaramaiah CR 2 , Jayana P. Lineswala 1 , Grace L. Neathery 1 , Cecilia Bouaichi 1 , Benjamin A. Diseroad 1 , Alison N. Campbell 1 , Stephanie A. Sweetana 1 , Lisa A. Adams 1 , Over Cabrera 1 , Xiaosu Ma 1 , Nathan P. Yumibe 1 , Chahrzad Montrose-Rafizadeh 1 , Yanyun Chen 1 , Anne Reifel Miller 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-01-05 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01411 Chafiq Hamdouchi 1 , Pranab Maiti 2 , Alan M. Warshawsky 1 , Amy C. DeBaillie 1 , Keith A. Otto 1 , Kelly L. Wilbur 1 , Steven D. Kahl 1 , Anjana Patel Lewis 1 , Guemalli R. Cardona 1 , Richard W. Zink 1 , Keyue Chen 1 , Siddaramaiah CR 2 , Jayana P. Lineswala 1 , Grace L. Neathery 1 , Cecilia Bouaichi 1 , Benjamin A. Diseroad 1 , Alison N. Campbell 1 , Stephanie A. Sweetana 1 , Lisa A. Adams 1 , Over Cabrera 1 , Xiaosu Ma 1 , Nathan P. Yumibe 1 , Chahrzad Montrose-Rafizadeh 1 , Yanyun Chen 1 , Anne Reifel Miller 1
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As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
中文翻译：
LY3104607的发现：具有优化的药代动力学特性的强效选择性G蛋白偶联受体40（GPR40）激动剂，可支持2型糖尿病患者每天一次的口服治疗
作为我们的程序，以确定能够被口头人类每日给药一次有效的GPR40激动剂的一部分，我们整合了稠合杂环到我们的最近公开的螺哌啶和四氢喹啉羧酸衍生物1，2，和3与降低清除率和提高了最大的意图可吸收剂量（Dabs）。假设驱动的结构修饰着重于远离两性离子结构。和减轻N-脱烷基和O-脱烷基的问题导致三唑并吡啶吡啶酸衍生物具有独特的药理学和优异的药代动力学特性。化合物4（LY3104607）证明了大鼠原发胰岛的功能效能和葡萄糖依赖性胰岛素分泌（GDIS）。在葡萄糖耐量试验（GTT）研究期间，观察到了葡萄糖水平的强力，有效和持久剂量依赖性降低。在所有物种中均观察到低清除率，分布体积和高口服生物利用度。增强的药理学和药代动力学性质的结合支持了该化合物作为潜在的降糖药物候选物的进一步开发。
更新日期：2018-01-05
中文翻译：
LY3104607的发现：具有优化的药代动力学特性的强效选择性G蛋白偶联受体40（GPR40）激动剂，可支持2型糖尿病患者每天一次的口服治疗
作为我们的程序，以确定能够被口头人类每日给药一次有效的GPR40激动剂的一部分，我们整合了稠合杂环到我们的最近公开的螺哌啶和四氢喹啉羧酸衍生物1，2，和3与降低清除率和提高了最大的意图可吸收剂量（Dabs）。假设驱动的结构修饰着重于远离两性离子结构。和减轻N-脱烷基和O-脱烷基的问题导致三唑并吡啶吡啶酸衍生物具有独特的药理学和优异的药代动力学特性。化合物4（LY3104607）证明了大鼠原发胰岛的功能效能和葡萄糖依赖性胰岛素分泌（GDIS）。在葡萄糖耐量试验（GTT）研究期间，观察到了葡萄糖水平的强力，有效和持久剂量依赖性降低。在所有物种中均观察到低清除率，分布体积和高口服生物利用度。增强的药理学和药代动力学性质的结合支持了该化合物作为潜在的降糖药物候选物的进一步开发。
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