title: Highly constrained bicyclic VLA-4 antagonists.
abstract: VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic beta-amino acids (beta-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (phi) between the amino and the carboxyl termini of the beta-aa. Compound 5 m where the beta-aa is embedded in a bicycle possesses the most preferred phi (120 degrees). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig alpha4beta1 IC50 = 54 nM, rat po F = 49%).
authors.affiliation: Department of Medicinal Chemical Research, Merck Research Laboratories, Rahway, NJ 07065, USA.
authors.forename: Linda L
authors.initials: LL
authors.lastname: Chang
authors.forename: Quang
authors.initials: Q
authors.lastname: Truong
authors.forename: George A
authors.initials: GA
authors.lastname: Doss
authors.forename: Malcolm
authors.initials: M
authors.lastname: MacCoss
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Ermengilda
authors.initials: E
authors.lastname: McCauley
authors.forename: Richard
authors.initials: R
authors.lastname: Mumford
authors.forename: Gail
authors.initials: G
authors.lastname: Forrest
authors.forename: Stella
authors.initials: S
authors.lastname: Vincent
authors.forename: John A
authors.initials: JA
authors.lastname: Schmidt
authors.forename: William K
authors.initials: WK
authors.lastname: Hagmann
mesh_terms: D001682:Biological Availability; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000378:metabolism; D019169:Jurkat Cells; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D001643:Bridged Bicyclo Compounds; D007202:Indicators and Reagents; D039041:Integrin alpha4beta1; D016023:Integrins; D019010:Vascular Cell Adhesion Molecule-1