Specific and dual antagonists of alpha(4)beta(1) and alpha(4)beta(7) integrins.
N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship.
Lin
Linus S
LS
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. linus_lin@merck.com
Lanza
Thomas
T
McCauley
Ermenegilda
E
Van Riper
Gail
G
Kidambi
Usha
U
Cao
Jin
J
Egger
Linda A
LA
Mumford
Richard A
RA
Schmidt
John A
JA
MacCoss
Malcolm
M
Hagmann
William K
WK
D000409:Alanine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology*
D039041:Integrin alpha4beta1; D016023:Integrins; C449666:N-(3,5-dichlorophenylsulfonyl)-thioprolyl biarylalanine; D016201:Receptors, Lymphocyte Homing; D013438:Sulfhydryl Compounds; C071777:integrin alpha4beta7; D000409:Alanine