2. Academic Validation
  3. Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1

Discovery of a Series of Pyrimidine Carboxamides as Inhibitors of Vanin-1

  • J Med Chem. 2022 Jan 13;65(1):757-784. doi: 10.1021/acs.jmedchem.1c01849.
Agustin Casimiro-Garcia 1,  Christophe Allais 2,  Agnes Brennan 3,  Chulho Choi 2,  Gabriela Dower 3,  Kathleen A Farley 2,  Margaret Fleming 3,  Andrew Flick 2,  Richard K Frisbie 2,  Justin Hall 2,  David Hepworth 1,  Hannah Jones 1,  John D Knafels 2,  Steve Kortum 2,  Frank E Lovering 1,  John P Mathias 1,  Sashi Mohan 3,  Paul M Morgan 3,  Chuenlei Parng 1,  Kevin Parris 2,  Nick Pullen 3,  Franklin Schlerman 3,  John Stansfield 4,  Joseph W Strohbach 1,  Felix F Vajdos 2,  Fabien Vincent 2,  Hong Wang 2,  Xiaolun Wang 1,  Robert Webster 1,  Stephen W Wright 2
Affiliations

Affiliations

  • 1 Medicine Design, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 2 Medicine Design, Pfizer Inc., 445 Eastern Point Rd, Groton, Connecticut 06340, United States.
  • 3 Inflammation and Immunology Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States.
  • 4 Early Clinical Development Non-Clinical Statistics, Pfizer Inc., 1 Portland Street, Cambridge, Massachusetts 02139, United States.
PMID: 34967602 DOI: 10.1021/acs.jmedchem.1c01849
Abstract

A diaryl ketone series was identified as vanin-1 inhibitors from a high-throughput screening campaign. While this novel scaffold provided valuable probe 2 that was used to build target confidence, concerns over the ketone moiety led to the replacement of this group. The successful replacement of this moiety was achieved with pyrimidine carboxamides derived from cyclic secondary amines that were extensively characterized using biophysical and crystallographic methods as competitive inhibitors of vanin-1. Through optimization of potency and physicochemical and ADME properties, and guided by co-crystal structures with vanin-1, 3 was identified with a suitable profile for advancement into preclinical development.

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