Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability. Issue 6 (15th March 2017)

• Record Type: Journal Article
• Authors: Hartz, Richard A.; Vrudhula, Vivekananda M.; Ahuja, Vijay T.; Grace, James E.; Lodge, Nicholas J.; Bronson, Joanne J.; Macor, John E.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 6(2017)
• Page Start: 1360
• Page End: 1363
• Publication Date: 2017-03-15
• Subjects: Corticotropin-releasing factor -- CRF -- Pyrazinone -- Prodrug; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.02.015
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: A series of phosphate and ester-based prodrugs of BMS-665053 was prepared and evaluated in rat pharmacokinetic studies with the goal of improving the oral bioavailability of the parent. Abstract: A series of phosphate and ester-based prodrugs of anilinopyrazinone1 (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 to1 . Prodrug12, 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.