Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure.

Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.

Identification of novel functional inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3).

BACKGROUND: Endocrine therapy of prostate cancer (PCa) relies on agents which disrupt the biosynthesis of testosterone in the testis and/or by direct antagonism of active hormone on the androgen receptor (AR) in non-gonadal target tissues of hormone action such as the prostate. METHODS: In an effort to evaluate new therapies which could inhibit gonadal or non-gonadal testosterone biosynthesis, we developed high throughput biochemical and cellular screening assays to identify inhibitors of 17beta-hydroxysteroid dehydrogenase type III (17beta-HSD3), the enzyme catalyzing the conversion of androstenedione (AdT) to testosterone. RESULTS: Initial screening efforts identified a natural product, 18beta-glycyrrhetinic acid, and a novel derivative of AdT, 3-O-benzylandrosterone, as potent inhibitors of the enzyme. Further efforts led to the identification of several classes of non-steroidal, low molecular weight compounds that potently inhibited 17beta-HSD3 enzymatic activity. One of the most potent classes of 17beta-HSD3 inhibitors was a series of anthranilamide small molecules identified from a collection of compounds related to non-steroidal modulators of nuclear hormone receptors. The anthranilamide based 17beta-HSD3 inhibitors were exemplified by BMS-856, a compound displaying low nanomolar inhibition of 17beta-HSD3 enzymatic activity. In addition, this series of compounds displayed potent inhibition of 17beta-HSD3-mediated cellular conversion of AdT to testosterone and inhibited the 17beta-HSD3-mediated conversion of testosterone necessary to promote AR-dependent transcription. CONCLUSIONS: The identification of non-steroidal functional inhibitors of 17beta-HSD3 may be a useful complementary approach for the disruption of testosterone biosynthesis in the treatment of PCa.