Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5'-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

  • J Med Chem. 2018 Mar 22;61(6):2372-2383. 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
Affiliations
  • 1. Pfizer Worldwide Research and Development , 610 Main Street , Cambridge , Massachusetts 02139 , United States.
  • 2. Pfizer Worldwide Research and Development , Eastern Point Road , Groton , Connecticut 06340 , United States.
Abstract

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.

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