Isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives as potent α4β1 integrin antagonists

被引：11

作者：

Duplantier, AJ ^{[1
]}

Beckius, GE ^{[1
]}

Chambers, RJ ^{[1
]}

Chupak, LS ^{[1
]}

Jenkinson, TH ^{[1
]}

Klein, AS ^{[1
]}

Kraus, KG ^{[1
]}

Kudlacz, EM ^{[1
]}

McKechney, MW ^{[1
]}

Pettersson, M ^{[1
]}

Whitney, CA ^{[1
]}

Milici, AJ ^{[1
]}

机构：

[1] Pfizer Global Res & Dev, Groton Labs, Groton, CT 06340 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 19期

关键词：

D O I：

10.1016/S0960-894X(01)00511-X

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha (4)beta (1) integrin. The synthesis and SAR leading up to 3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported, In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib ((a) over bar; 10 mg/kg, sc) as well as by intra-tracheal instillation (ED50 = 2 mug/kg). (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：2593 / 2596

页数：4

共 21 条

[1] A small-molecule, tight-binding inhibitor of the integrin α4β1 blocks antigen-induced airway responses and inflammation in experimental asthma in sheep [J].

Abraham, WM ;

Gill, A ;

Ahmed, A ;

Sielczak, MW ;

Lauredo, IT ;

Botinnikova, Y ;

Lin, KC ;

Pepinsky, B ;

Leone, DR ;

Lobb, RR ;

Adams, SP .

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2000, 162 (02) :603-611

[2] ALPHA(4)-INTEGRINS MEDIATE ANTIGEN-INDUCED LATE BRONCHIAL RESPONSES AND PROLONGED AIRWAY HYPERRESPONSIVENESS IN SHEEP [J].

ABRAHAM, WM ;

SIELCZAK, MW ;

AHMED, A ;

CORTES, A ;

LAUREDO, IT ;

KIM, J ;

PEPINSKY, B ;

BENJAMIN, CD ;

LEONE, DR ;

LOBB, RR ;

WELLER, PF .

JOURNAL OF CLINICAL INVESTIGATION, 1994, 93 (02) :776-787

[3] AN EFFICIENT SYNTHESIS OF ETHYL 5-OXAZOLEACETATES [J].

DOW, RL .

JOURNAL OF ORGANIC CHEMISTRY, 1990, 55 (01) :386-388

[4] LYMPHOID-CELLS RECOGNIZE AN ALTERNATIVELY SPLICED SEGMENT OF FIBRONECTIN VIA THE INTEGRIN RECEPTOR-ALPHA-4-BETA-1 [J].

GUAN, JL ;

HYNES, RO .

CELL, 1990, 60 (01) :53-61

[5]

HASHIGUCHI S, 1992, SYNTHESIS-STUTTGART, P403

[6] VLA PROTEINS IN THE INTEGRIN FAMILY - STRUCTURES, FUNCTIONS, AND THEIR ROLE ON LEUKOCYTES [J].

HEMLER, ME .

ANNUAL REVIEW OF IMMUNOLOGY, 1990, 8 :365-400

[7] The relevance of murine animal models to study the development of allergic bronchial asthma [J].

Herz, U ;

Lumpp, U ;

DaPalma, JC ;

Enssle, K ;

Takatsu, K ;

Schnoy, N ;

Daser, A ;

Kottgen, E ;

Wahn, U ;

Renz, H .

IMMUNOLOGY AND CELL BIOLOGY, 1996, 74 (02) :209-217

[8]

JONES R, 1999, SYNLETT S, V1, P873

[9] A MONOCLONAL-ANTIBODY TO ALPHA-4 INTEGRIN SUPPRESSES AND REVERSES ACTIVE EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS [J].

KENT, SJ ;

KARLIK, SJ ;

CANNON, C ;

HINES, DK ;

YEDNOCK, TA ;

FRITZ, LC ;

HORNER, HC .

JOURNAL OF NEUROIMMUNOLOGY, 1995, 58 (01) :1-10

[10]

KOMORIYA A, 1991, J BIOL CHEM, V266, P15075

← 1 2 3 →