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
  • 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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