title: Influence of acid surrogates toward potency of VLA-4 antagonist.
abstract: A series of VLA-4 antagonist were synthesized wherein carboxylic acid was replaced by various acid surrogates. The effect of these acid surrogates toward potency was evaluated in a binding assay. A number of acid surrogates were potent antagonist of VLA-4, albeit significantly less potent than the corresponding carboxylic acid. Heterocyclic acid surrogate, oxadiazolidinone 3, demonstrated an improved pharmacokinetic property when dosed intravenously.
authors.affiliation: Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. shankar_venkatraman@merck.com
authors.forename: Shankar
authors.initials: S
authors.lastname: Venkatraman
authors.forename: Jongwon
authors.initials: J
authors.lastname: Lim
authors.forename: Merryl
authors.initials: M
authors.lastname: Cramer
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gardner
authors.forename: Joyce
authors.initials: J
authors.lastname: James
authors.forename: Kenneth
authors.initials: K
authors.lastname: Alves
authors.forename: Russell B
authors.initials: RB
authors.lastname: Lingham
authors.forename: Richard A
authors.initials: RA
authors.lastname: Mumford
authors.forename: Benito
authors.initials: B
authors.lastname: Munoz
mesh_terms: D000143:Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D020128:Inhibitory Concentration 50; D007275:Injections, Intravenous; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D010069:Oxadiazoles / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000143:Acids; D039041:Integrin alpha4beta1; D010069:Oxadiazoles