Piperidine-containing beta-arylpropionic acids as potent antagonists of alphavbeta3/alphavbeta5 integrins.
The synthesis and SAR of a new class of piperidine-based alphavbeta3/alphavbeta5 integrin antagonists is described. Replacement of an amide bond in a prototype isonipecotamide by a C-C isostere, and adjustment of the spacer length between the carboxylic acid and basic moieties, led to low nanomolar antagonists of alphavbeta3 and/or alphavbeta5 integrins with excellent selectivity versus alpha(IIb)beta3.
De Corte
Bart L
BL
Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, Welsh & McKean Roads, Spring House, PA 19477-0776, USA. bdecorte@prdus.jnj.com
Kinney
William A
WA
Liu
Li
L
Ghosh
Shyamali
S
Brunner
Livia
L
Hoekstra
William J
WJ
Santulli
Rosemary J
RJ
Tuman
Robert W
RW
Baker
Judith
J
Burns
Candace
C
Proost
Jef C
JC
Tounge
Brett A
BA
Damiano
Bruce P
BP
Maryanoff
Bruce E
BE
Johnson
Dana L
DL
Galemmo
Robert A
RA
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011422:Propionates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
D039302:Integrin alphaVbeta3; D016023:Integrins; D010880:Piperidines; D011422:Propionates; D019030:Receptors, Vitronectin; C064660:integrin alphaVbeta5