Influence of acid surrogates toward potency of VLA-4 antagonist.
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.
Venkatraman
Shankar
S
Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. shankar_venkatraman@merck.com
Lim
Jongwon
J
Cramer
Merryl
M
Gardner
Michael F
MF
James
Joyce
J
Alves
Kenneth
K
Lingham
Russell B
RB
Mumford
Richard A
RA
Munoz
Benito
B
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
D000143:Acids; D039041:Integrin alpha4beta1; D010069:Oxadiazoles