title: Heterocycle-substituted proline dipeptides as potent VLA-4 antagonists.
abstract: A variety of N-linked tertiary amines and heteroarylamines were examined at the 4-position of sulfonylated proline dipeptides in order to improve VLA-4 receptor off-rates and overcome the issue of CYP3A4 time-dependent inhibition of ester prodrugs. A tight-binding inhibitor 5j with a long off-rate provided sustained receptor occupancy despite poor oral pharmacokinetics.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, San Diego, CA 92121, USA. thomas_reger@merck.com
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reger
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zunic
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Bowei
authors.initials: B
authors.lastname: Wang
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Smith
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
authors.forename: Mitchell D
authors.initials: MD
authors.lastname: Green
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Joyce P
authors.initials: JP
authors.lastname: James
authors.forename: Weichao
authors.initials: W
authors.lastname: Chen
authors.forename: Kenneth
authors.initials: K
authors.lastname: Alves
authors.forename: Qian
authors.initials: Q
authors.lastname: Si
authors.forename: Kelly M
authors.initials: KM
authors.lastname: Treonze
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011392:Proline / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000502:physiology; D051381:Rats
chemical_list: D004151:Dipeptides; D006571:Heterocyclic Compounds; D039041:Integrin alpha4beta1; D011392:Proline