2. Academic Validation
  3. 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.
PMID: 29466005 DOI: 10.1021/acs.jmedchem.7b01641
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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