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Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01641 David J. Edmonds 1 , Daniel W. Kung 2 , Amit S. Kalgutkar 1 , Kevin J. Filipski 1 , David C. Ebner 1 , Shawn Cabral 2 , Aaron C. Smith 2 , Gary E. Aspnes 2 , Samit K. Bhattacharya 1 , Kris A. Borzilleri 2 , Janice A. Brown 2 , Matthew F. Calabrese 2 , Nicole L. Caspers 2 , Emily C. Cokorinos 1 , Edward L. Conn 2 , Matthew S. Dowling 2 , Heather Eng 2 , Bo Feng 2 , Dilinie P. Fernando 2 , Nathan E. Genung 2 , Michael Herr 2 , Ravi G. Kurumbail 2 , Sophie Y. Lavergne 2 , Esther C.-Y. Lee 1 , Qifang Li 2 , Sumathy Mathialagan 2 , Russell A. Miller 1 , Jane Panteleev 2 , Jana Polivkova 2 , Francis Rajamohan 2 , Allan R. Reyes 1 , Christopher T. Salatto 1 , Andre Shavnya 2 , Benjamin A. Thuma 2 , Meihua Tu 1 , Jessica Ward 1 , Jane M. Withka 2 , Jun Xiao 2 , Kimberly O. Cameron 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-02-21 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01641 David J. Edmonds 1 , Daniel W. Kung 2 , Amit S. Kalgutkar 1 , Kevin J. Filipski 1 , David C. Ebner 1 , Shawn Cabral 2 , Aaron C. Smith 2 , Gary E. Aspnes 2 , Samit K. Bhattacharya 1 , Kris A. Borzilleri 2 , Janice A. Brown 2 , Matthew F. Calabrese 2 , Nicole L. Caspers 2 , Emily C. Cokorinos 1 , Edward L. Conn 2 , Matthew S. Dowling 2 , Heather Eng 2 , Bo Feng 2 , Dilinie P. Fernando 2 , Nathan E. Genung 2 , Michael Herr 2 , Ravi G. Kurumbail 2 , Sophie Y. Lavergne 2 , Esther C.-Y. Lee 1 , Qifang Li 2 , Sumathy Mathialagan 2 , Russell A. Miller 1 , Jane Panteleev 2 , Jana Polivkova 2 , Francis Rajamohan 2 , Allan R. Reyes 1 , Christopher T. Salatto 1 , Andre Shavnya 2 , Benjamin A. Thuma 2 , Meihua Tu 1 , Jessica Ward 1 , Jane M. Withka 2 , Jun Xiao 2 , Kimberly O. Cameron 1
Affiliation
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Optimization of the pharmacokinetic (PK) properties of a series of activators of adenosine monophosphate-activated protein kinase (AMPK) is described. Derivatives of the previously described 5-aryl-indole-3-carboxylic acid clinical candidate (1) were examined with the goal of reducing glucuronidation rate and minimizing renal excretion. Compounds 10 (PF-06679142) and 14 (PF-06685249) exhibited robust activation of AMPK in rat kidneys as well as desirable oral absorption, low plasma clearance, and negligible renal clearance in preclinical species. A correlation of in vivo renal clearance in rats with in vitro uptake by human and rat renal organic anion transporters (human OAT/rat Oat) was identified. Variation of polar functional groups was critical to mitigate active renal clearance mediated by the Oat3 transporter. Modification of either the 6-chloroindole core to a 4,6-difluoroindole or the 5-phenyl substituent to a substituted 5-(3-pyridyl) group provided improved metabolic stability while minimizing propensity for active transport by OAT3.
中文翻译：
一系列5'-腺苷单磷酸激活蛋白激酶（AMPK）吲哚酸直接激活剂的代谢和肾清除率的优化
描述了一系列单磷酸腺苷活化蛋白激酶（AMPK）激活剂的药代动力学（PK）特性的优化。为了降低葡萄糖醛酸化率并最小化肾脏排泄，对先前描述的5-芳基-吲哚-3-羧酸临床候选药物（1）的衍生物进行了检查。化合物10（PF-06679142）和14（PF-06685249）在大鼠肾脏中显示出AMPK的强活化，以及在临床前物种中具有所需的口服吸收，低血浆清除率和可忽略的肾脏清除率。鉴定了大鼠体内肾清除率与人和大鼠肾有机阴离子转运蛋白（人OAT /大鼠燕麦）的体外摄取的相关性。极性功能基团的变化对于减轻由Oat3转运蛋白介导的活动性肾脏清除至关重要。将6-氯吲哚核心修饰为4,6-二氟吲哚或将5-苯基取代基修饰为取代的5-（3-吡啶基）基团可改善代谢稳定性，同时最大程度降低OAT3主动转运的可能性。
更新日期：2018-02-21
中文翻译：
一系列5'-腺苷单磷酸激活蛋白激酶（AMPK）吲哚酸直接激活剂的代谢和肾清除率的优化
描述了一系列单磷酸腺苷活化蛋白激酶（AMPK）激活剂的药代动力学（PK）特性的优化。为了降低葡萄糖醛酸化率并最小化肾脏排泄，对先前描述的5-芳基-吲哚-3-羧酸临床候选药物（1）的衍生物进行了检查。化合物10（PF-06679142）和14（PF-06685249）在大鼠肾脏中显示出AMPK的强活化，以及在临床前物种中具有所需的口服吸收，低血浆清除率和可忽略的肾脏清除率。鉴定了大鼠体内肾清除率与人和大鼠肾有机阴离子转运蛋白（人OAT /大鼠燕麦）的体外摄取的相关性。极性功能基团的变化对于减轻由Oat3转运蛋白介导的活动性肾脏清除至关重要。将6-氯吲哚核心修饰为4,6-二氟吲哚或将5-苯基取代基修饰为取代的5-（3-吡啶基）基团可改善代谢稳定性，同时最大程度降低OAT3主动转运的可能性。
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