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

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

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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