The retinoic acid receptor-α (RARα) is a nuclear receptor that has been implicated in male contraception. In the absence of retinoic acid, RARα has been shown to prevent spermatogenesis by inhibiting DNA transcription.1 Previous work by Bristol Myers Squibb identified two RAR antagonists of interest: BMS 189453 and BMS 189532 (Figure 1). While BMS 189453 has been shown to cause reversible infertility in mice when administered orally, it is non-selective over the β and γ isoforms; BMS 189532 is selective for RARα, but lacks oral bioavailability. The goal of this project is to design and synthesize selective, bioavailable antagonists of RARα based on the BMS scaffold, which can be broken down into three regions: a hydrophobic ring, a linker, and a carboxylic acid. The antagonists are tested using an iterative design process. The first generation of compounds developed in our lab contained varying aryl substituents on the ring region and amide bioisosteres in the linker region. The compounds were evaluated using protein crystallography, isothermal titration calorimetry, and a luciferase reporter assay. Analysis of the RARα co-crystal structures determined that additional lipophilic substituents on the ring portion of the scaffold could increase selectivity. Alternative ring structures, including chromenes, are being pursued. Synthesis and evaluation of these compounds will be discussed. References 1. Chung, S. S. W.; Cuellar, R. A. D.; Wang, X.; Reczek, P. R.; Georg, G. I.; Wolgemuth, D. J. ACS Med. Chem. Lett. 2013, 4, 446-450.

Design and synthesis of nuclear receptor antagonists targeting RARα for male contraception

251st National Meeting (2016)

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