Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability.

Richard A Hartz, Vivekananda M Vrudhula, Vijay T Ahuja, James E Grace, Nicholas J Lodge, Joanne J Bronson, John E Macor

Bioorganic & medicinal chemistry letters 2017 Mar 15

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A series of phosphate and ester-based prodrugs of anilinopyrazinone 1 (BMS-665053) containing either a methylene or an (acyloxy)alkoxy linker was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent (1). The prodrugs, in general, had improved aqueous solubility and oral bioavailability compared to 1. Prodrug 12, which contains an (acyloxy)alkoxy linker, showed the greatest improvement in the oral bioavailability relative to the parent (1), with a seven-fold increase (from 5% to 36%) in rat pharmacokinetic studies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Richard A Hartz, Vivekananda M Vrudhula, Vijay T Ahuja, James E Grace, Nicholas J Lodge, Joanne J Bronson, John E Macor. Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability. Bioorganic & medicinal chemistry letters. 2017 Mar 15;27(6):1360-1363