Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent alpha(4)beta(1) integrin antagonists.
A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).
Duplantier
A J
AJ
Pfizer Global Research and Development, Groton Labs, Eastern Point Road, Groton, CT 06340, USA. allen_j_duplantier@groton.pfizer.com
Beckius
G E
GE
Chambers
R J
RJ
Chupak
L S
LS
Jenkinson
T H
TH
Klein
A S
AS
Kraus
K G
KG
Kudlacz
E M
EM
McKechney
M W
MW
Pettersson
M P
MP
Whitney
C A
CA
Milici
A J
AJ
D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D007555:Isoxazoles / Q000494:pharmacology*; D019169:Jurkat Cells; D051379:Mice; D011422:Propionates / Q000494:pharmacology*; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C439163:3-(3-(1-(-(3-methoxy-4-(3-o-tolyl-ureido)-phenyl)-acetylamino)-3-methyl-butyl)-isoxazol-5-yl)-propionic acid; D039041:Integrin alpha4beta1; D016023:Integrins; D007555:Isoxazoles; D011422:Propionates; D016201:Receptors, Lymphocyte Homing