title: Synthesis and evaluation of prodrugs of corticotropin-releasing factor-1 (CRF1) receptor antagonist BMS-665053 leading to improved oral bioavailability.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: richard.hartz@bms.com.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hartz
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Vivekananda M
authors.initials: VM
authors.lastname: Vrudhula
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Vijay T
authors.initials: VT
authors.lastname: Ahuja
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Grace
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Research and Development, Bristol-Myers Squibb Company, 5 Research Parkway, Wallingford, CT 06492, USA.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000818:Animals; D001682:Biological Availability; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors*; D000099052:CRF Receptor, Type 1
chemical_list: C547831:BMS 665053; D011355:Prodrugs; D011719:Pyrazines; D018019:Receptors, Corticotropin-Releasing Hormone; D000099052:CRF Receptor, Type 1
keywords: CRF; Corticotropin-releasing factor; Prodrug; Pyrazinone