title: Bioisosteric replacement of anilide with benzoxazole: potent and orally bioavailable antagonists of VLA-4.
abstract: We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. linus_lin@merck.com
authors.forename: Linus S
authors.initials: LS
authors.lastname: Lin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Lanza
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Castonguay
authors.forename: Theodore
authors.initials: T
authors.lastname: Kamenecka
authors.forename: Ermenegilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Gail
authors.initials: G
authors.lastname: Van Riper
authors.forename: Linda A
authors.initials: LA
authors.lastname: Egger
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Xinchun
authors.initials: X
authors.lastname: Tong
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D000813:Anilides / Q000737:chemistry*; D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry*; D001682:Biological Availability; D006860:Hydrogen Bonding; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D000813:Anilides; D001583:Benzoxazoles; D039041:Integrin alpha4beta1