Lead generation from N-[benzyl(4-phenylbutyl)carbamoyl]amino acid as a novel LPA1 antagonist for the treatment of systemic sclerosis.

Lysophosphatidic acid (LPA), a bioactive phospholipid, binds to the G protein-coupled LPA1 receptor on the surfaces of immune cells, to promote progression of fibrosis of the skin and organs through inducing infiltration of immune cells into tissues, chemokine production, inflammatory cytokine production, and fibroblast transformation. Anti-fibrotic effects of LPA1 blockade have been reported in animal models of scleroderma and scleroderma patients. In the study reported herein, we identified the novel urea compound 5 as a hit compound with LPA1 antagonist activity from our in-house library and synthesized the lead compound TP0541640 (18) by structural transformation utilizing a structure-based drug design (SBDD) approach. Compound 18 possessed potent in vitro LPA1 antagonist activity and exhibited a dose-dependent inhibitory effect against LPA-induced histamine release in mice. Furthermore, 18 significantly suppressed collagen production and skin thickening in a mouse model of bleomycin-induced skin fibrosis. Herein, we describe the compound design strategies and in vivo studies in greater detail.