Optimization of activity, selectivity, and liability profiles in 5-oxopyrrolopyridine DPP4 inhibitors leading to clinical candidate (Sa)-2-(3-(aminomethyl)-4-(2,4-dichlorophenyl)-2-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)-N,N-dimethylacetamide (BMS-767778)

  • J Med Chem. 2013 Sep 26;56(18):7343-57. doi: 10.1021/jm4008906.
Pratik Devasthale  1 ,  Ying Wang ,  Wei Wang ,  John Fevig ,  JianXin Feng ,  Aiying Wang ,  Tom Harrity ,  Don Egan ,  Nathan Morgan ,  Michael Cap ,  Aberra Fura ,  Herbert E Klei ,  Kevin Kish ,  Carolyn Weigelt ,  Lucy Sun ,  Paul Levesque ,  Frederic Moulin ,  Yi-Xin Li ,  Robert Zahler ,  Mark S Kirby ,  Lawrence G Hamann
Affiliations
  • 1. Metabolic Diseases Chemistry, ‡Metabolic Diseases Biology, §Pharmaceutical Candidate Optimization, ∥Protein Science and Structure, ⊥Computer-Assisted Drug Design, Bristol-Myers Squibb Research and Development , Princeton, New Jersey 08543-5400, United States.
PMID: 23964740 DOI: 10.1021/jm4008906
Abstract

Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.

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