Aza-bicyclic amino acid carboxamides as alpha4beta1/alpha4beta7 integrin receptor antagonists.
A series of N-carboxy, N-alkyl, and N-carboxamido azabicyclo[2.2.2]octane carboxamides were prepared and assayed for inhibition of alpha4beta1-VCAM-1 and alpha4beta7-MAdCAM-1 interactions. Potency and alpha4beta1/alpha4beta7 selectivity were sensitive to the substituent R1-R3 in the structures 6, 7, and 8. Several compounds demonstrated low nanomolar balanced alpha4beta1/alpha4beta7 in vitro activity. Two compounds were selected for in vivo leukocytosis studies and demonstrated increases in circulating lymphocytes up to 250% over control.
Dyatkin
Alexey B
AB
Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC., Spring House, PA 19477-0776, USA. adyatkin@prdus.jnj.com
Gong
Yong
Y
Miskowski
Tamara A
TA
Kimball
Edward S
ES
Prouty
Stephen M
SM
Fisher
M Carolyn
MC
Santulli
Rosemary J
RJ
Schneider
Craig R
CR
Wallace
Nathaniel H
NH
Hornby
Pamela J
PJ
Diamond
Craig
C
Kinney
William A
WA
Maryanoff
Bruce E
BE
Damiano
Bruce P
BP
He
Wei
W
D000598:Amino Acids, Cyclic / Q000737:chemistry*; D000818:Animals; D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007964:Leukocytosis; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship
D000598:Amino Acids, Cyclic; D001372:Aza Compounds; D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7