Discovery of an
Oxycyclohexyl Acid Lysophosphatidic
Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment
of Pulmonary Fibrotic Diseases

Cheng, Peter T. W.; Kaltenbach, Robert F.; Zhang, Hao; Shi, Jun; Tao, Shiwei; Li, Jun; Kennedy, Lawrence J.; Walker, Steven J.; Shi, Yan; Wang, Ying; Dhanusu, Suresh; Reddigunta, Ramesh; Kumaravel, Selvakumar; Jusuf, Sutjano; Smith, Daniel; Krishnananthan, Subramaniam; Li, Jianqing; Wang, Tao; Heiry, Rebekah; Sum, Chi Shing; Kalinowski, Stephen S.; Hung, Chen-Pin; Chu, Ching-Hsuen; Azzara, Anthony V.; Ziegler, Milinda; Burns, Lisa; Zinker, Bradley A.; Boehm, Stephanie; Taylor, Joseph; Sapuppo, Julia; Mosure, Kathy; Everlof, Gerry; Guarino, Victor; Zhang, Lisa; Yang, Yanou; Ruan, Qian; Xu, Carrie; Apedo, Atsu; Traeger, Sarah C.; Cvijic, Mary Ellen; Lentz, Kimberley A.; Tirucherai, Giridhar; Sivaraman, Lakshmi; Robl, Jeffrey; Ellsworth, Bruce A.; Rosen, Glenn; Gordon, David A.; Soars, Matthew G.; Gill, Michael; Murphy, Brian J.

doi:10.1021/acs.jmedchem.1c01256.s001

jm1c01256_si_001.pdf (731.09 kB)

Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA₁) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases

journal contribution

posted on 2021-10-28, 18:46 authored by Peter T. W. Cheng, Robert F. Kaltenbach, Hao Zhang, Jun Shi, Shiwei Tao, Jun Li, Lawrence J. Kennedy, Steven J. Walker, Yan Shi, Ying Wang, Suresh Dhanusu, Ramesh Reddigunta, Selvakumar Kumaravel, Sutjano Jusuf, Daniel Smith, Subramaniam Krishnananthan, Jianqing Li, Tao Wang, Rebekah Heiry, Chi Shing Sum, Stephen S. Kalinowski, Chen-Pin Hung, Ching-Hsuen Chu, Anthony V. Azzara, Milinda Ziegler, Lisa Burns, Bradley A. Zinker, Stephanie Boehm, Joseph Taylor, Julia Sapuppo, Kathy Mosure, Gerry Everlof, Victor Guarino, Lisa Zhang, Yanou Yang, Qian Ruan, Carrie Xu, Atsu Apedo, Sarah C. Traeger, Mary Ellen Cvijic, Kimberley A. Lentz, Giridhar Tirucherai, Lakshmi Sivaraman, Jeffrey Robl, Bruce A. Ellsworth, Glenn Rosen, David A. Gordon, Matthew G. Soars, Michael Gill, Brian J. Murphy

The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA₁) antagonist, with a human LPA₁ K_b of 6.9 nM. The structure–activity relationship (SAR) studies starting from the LPA₁ antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).