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.

Products