2. Academic Validation
  3. Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK

Driving Potency with Rotationally Stable Atropisomers: Discovery of Pyridopyrimidinedione-Carbazole Inhibitors of BTK

  • ACS Med Chem Lett. 2020 Sep 16;11(11):2195-2203. doi: 10.1021/acsmedchemlett.0c00335.
Anurag S Srivastava 1,  Soo Ko 1,  Scott H Watterson 1,  Mark A Pattoli 1,  Stacey Skala 1,  Lihong Cheng 1,  Mary T Obermeier 1,  Rodney Vickery 1,  Lorell N Discenza 1,  Celia J D'Arienzo 1,  Kathleen M Gillooly 1,  Tracy L Taylor 1,  Claudine Pulicicchio 1,  Kim W McIntyre 1,  Shiuhang Yip 1,  Peng Li 1,  Dawn Sun 1,  Dauh-Rurng Wu 1,  Jun Dai 1,  Chunlei Wang 1,  Yingru Zhang 1,  Bei Wang 1,  Joseph Pawluczyk 1,  James Kempson 1,  Rulin Zhao 1,  Xiaoping Hou 1,  Richard Rampulla 1,  Arvind Mathur 1,  Michael A Galella 1,  Luisa Salter-Cid 1,  Joel C Barrish 1,  Percy H Carter 1,  Aberra Fura 1,  James R Burke 1,  Joseph A Tino 1
Affiliations

Affiliation

  • 1 Bristol Myers Squibb Research and Early Development, P.O. Box 4000, Princeton, New Jersey 08543, United States.
PMID: 33214829 DOI: 10.1021/acsmedchemlett.0c00335
Abstract

Bruton's tyrosine kinase (Btk) has been shown to play a key role in the pathogenesis of autoimmunity. Therefore, the inhibition of the kinase activity of Btk with a small molecule inhibitor could offer a breakthrough in the clinical treatment of many autoimmune diseases. This Letter describes the discovery of BMS-986143 through systematic structure-activity relationship (SAR) development. This compound benefits from defined chirality derived from two rotationally stable atropisomeric axes, providing a potent and selective single atropisomer with desirable efficacy and tolerability profiles.

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