Synthesis and biological evaluation of novel pyridazinone-based α4 integrin receptor antagonists

被引：34

作者：

Gong, Yong ^{[1
]}

Barbay, J. Kent ^{[1
]}

Dyatkin, Alexey B. ^{[1
]}

Miskowski, Tamara A. ^{[1
]}

Kimball, Edward S. ^{[1
]}

Prouty, Stephen M. ^{[1
]}

Fisher, M. Carolyn ^{[1
]}

Santulli, Rosemary J. ^{[1
]}

Schneider, Craig R. ^{[1
]}

Wallace, Nathaniel H. ^{[1
]}

Ballentine, Scott A. ^{[1
]}

Hageman, William E. ^{[1
]}

Masucci, John A. ^{[1
]}

Maryanoff, Bruce E. ^{[1
]}

Damiano, Bruce P. ^{[1
]}

Andrade-Gordon, Patricia ^{[1
]}

Hlasta, Dennis J. ^{[1
]}

Hornby, Pamela J. ^{[1
]}

He, Wei ^{[1
]}

机构：

[1] Johnson & Johnson Pharmaceut Res & Dev LLC, Drug Discovery, Spring House, PA 19477 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 11期

关键词：

D O I：

10.1021/jm060031q

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of pyridazinone-functionalized phenylalanine analogues was prepared and evaluated for inhibition of cellular adhesion mediated by alpha(4)beta(1)/VCAM-1 and alpha(4)beta(7)/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 alpha(4)beta(1) and alpha(4)beta(7) were generated from an amide subseries; antagonists selective for alpha(4)beta(7) 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 alpha(4),beta(7)-selective member of the carbamate subseries (36c), upon oral admininstration, demonstrated in vivo efficacy in the mouse DSS colitis model.

引用

页码：3402 / 3411

页数：10

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