title: Aza-bicyclic amino acid carboxamides as alpha4beta1/alpha4beta7 integrin receptor antagonists.
abstract: 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.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, LLC., Spring House, PA 19477-0776, USA. adyatkin@prdus.jnj.com
authors.forename: Alexey B
authors.initials: AB
authors.lastname: Dyatkin
authors.forename: Yong
authors.initials: Y
authors.lastname: Gong
authors.forename: Tamara A
authors.initials: TA
authors.lastname: Miskowski
authors.forename: Edward S
authors.initials: ES
authors.lastname: Kimball
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Prouty
authors.forename: M Carolyn
authors.initials: MC
authors.lastname: Fisher
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Santulli
authors.forename: Craig R
authors.initials: CR
authors.lastname: Schneider
authors.forename: Nathaniel H
authors.initials: NH
authors.lastname: Wallace
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hornby
authors.forename: Craig
authors.initials: C
authors.lastname: Diamond
authors.forename: William A
authors.initials: WA
authors.lastname: Kinney
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Wei
authors.initials: W
authors.lastname: He
mesh_terms: 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
chemical_list: D000598:Amino Acids, Cyclic; D001372:Aza Compounds; D039041:Integrin alpha4beta1; D016023:Integrins; C071777:integrin alpha4beta7