title: Synthesis and biological evaluation of novel pyridazinone-based alpha4 integrin receptor antagonists.
abstract: A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha4beta1/VCAM-1 and alpha4beta7/MAdCAM-1 interactions. Concise syntheses were developed and applied for exploration of structure-activity relationships pertaining to the pyridazinone ring as well as the N-acyl phenylalanine scaffold. Potent dual antagonists of alpha4beta1 and alpha4beta7 were generated from an amide subseries; antagonists selective for alpha4beta7 were identified from urea and carbamate-based subseries. The pharmacokinetic properties of selected members of the series have been determined in rats and demonstrate that the use of ester prodrugs and alterations to the amide linkage can lead to improved oral bioavailability in this series. An alpha4beta7-selective member of the carbamate subseries (36c), upon oral administration, demonstrated in vivo efficacy in the mouse DSS colitis model.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Welsh & McKean Roads, P.O. Box 776, Spring House, Pennsylvania 19477, USA. ygong@prdus.jnj.com
authors.forename: Yong
authors.initials: Y
authors.lastname: Gong
authors.forename: J Kent
authors.initials: JK
authors.lastname: Barbay
authors.forename: Alexey B
authors.initials: AB
authors.lastname: Dyatkin
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: Scott A
authors.initials: SA
authors.lastname: Ballentine
authors.forename: William E
authors.initials: WE
authors.lastname: Hageman
authors.forename: John A
authors.initials: JA
authors.lastname: Masucci
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Damiano
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Dennis J
authors.initials: DJ
authors.lastname: Hlasta
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hornby
authors.forename: Wei
authors.initials: W
authors.lastname: He
mesh_terms: D000818:Animals; D001682:Biological Availability; D002448:Cell Adhesion / Q000187:drug effects; D015815:Cell Adhesion Molecules; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy; D016264:Dextran Sulfate; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007136:Immunoglobulins / Q000378:metabolism; D066298:In Vitro Techniques; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020014:K562 Cells; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000502:physiology; D009088:Mucoproteins / Q000378:metabolism; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: C511641:2-tert-butoxycarbonylamino-3-(4-(2-(2-hydroxyethyl)-5-methoxy-3-oxo-2,3-dihydropyridazin-4-yl)phenyl)propionic acid 2-hydroxyethyl ester; D015815:Cell Adhesion Molecules; D004952:Esters; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D011355:Prodrugs; D011724:Pyridazines; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7; D010649:Phenylalanine; D016264:Dextran Sulfate