Discovery and Anti-fibrotic Activity of Novel Antagonists of Lysophosphatidic Acid Receptor 1 (LPA1)

J.B. Nicholas 1 , J.-X. Huang 1 , L. Hooi 1 , C. Schaefer 1 , L. Pan 1 , L. Huang 1 , S. Yap 1 , H. Ramesha 1 , K. Kossen 1 , K. Emayan 1 , S. Misialek 1 , R. Rajagopalan 1 , K. Dolim 1 , C. Zhen 1 , M. Hu 1 , J. Henshilwood 1 , R. Radhakrishnan 1 , S. Sastry 1 , A.M. Tager 2 , F.V. Castelino 2 , S.D. Seiwert 1 , B.O. Buckman 1 1 InterMune, Inc., Brisbane, CA and 2 Massachusetts General Hospital, Charlestown, MA Background : Lysophosphatidic acid (LPA), through stimulation of its G-protein coupled receptor lysophosphatidic acid receptor 1 (LPA 1 ), has been identified as an important mediator of fibrosis.  Currently, two LPA 1 receptor antagonists are in clinical trials for IPF and for systemic sclerosis.  Next generation LPA 1 receptor antagonists with improved properties may represent important new anti-fibrotic agents.  Here, we describe the performance characteristics of ITMN-10534, a potential best-in-class small molecule LPA 1 antagonist. Methods : Structure-guided rational drug design using an LPA 1 receptor homology model and a computational scaffold-hopping approach was used to design novel antagonists.  The resultant compounds were screened for LPA 1 receptor antagonism, selectivity against other LPA and S1P receptors, inhibition of fibroblast migration, and inhibition of fibroblast proliferation.  Select series were optimized for in vitro ADME, oral exposure in preclinical species, and safety properties.  Lead compounds were evaluated for antagonist activity in a model of LPA-induced histamine release and efficacy in models of fibrosis. Results : Multiple series of novel LPA 1 antagonists displayed nanomolar antagonism of LPA-induced Ca 2+ flux and inhibition of fibroblast migration and proliferation.  Optimized members of several series exhibited high metabolic stability in liver microsomes and hepatocytes, and favorable pharmacokinetics in preclinical species following oral administration.  ITMN-10534 showed activity in an LPA-induced histamine release PD model and in bleomycin-induced models of both pulmonary and skin fibrosis. Conclusions: Potent selective, orally active LPA 1 antagonists have been designed.  ITMN-10534 is an IND-development candidate and is now advancing towards the clinic.