NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .6. DESIGN OF A POTENT, INTRATRACHEALLY ACTIVE, PYRIDONE-BASED TRIFLUOROMETHYL KETONE

被引：47

作者：

BERNSTEIN, PR ^{[1
]}

GOMES, BC ^{[1
]}

KOSMIDER, BJ ^{[1
]}

VACEK, EP ^{[1
]}

WILLIAMS, JC ^{[1
]}

机构：

[1] ZENECA PHARMACEUT,DEPT PHARMACOL,WILMINGTON,DE 19897

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1995年 / 38卷 / 01期

关键词：

D O I：

10.1021/jm00001a028

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Further modification of the 3-amino substituent in a trifluoromethyl ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlorophenyl) sulfonyl]carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED(50) of similar to 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355.

引用

页码：212 / 215

页数：4

共 15 条

[1]

BERGESON S, 1990, Patent No. 4910190

[2]

BERGESON SH, 1987, 193RD NAT M AM CHEM

[3]

Bernstein P R, 1994, Prog Med Chem, V31, P59, DOI 10.1016/S0079-6468(08)70019-5

[4] NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .3. DESIGN, SYNTHESIS, X-RAY CRYSTALLOGRAPHIC ANALYSIS, AND STRUCTURE-ACTIVITY-RELATIONSHIPS FOR A SERIES OF ORALLY-ACTIVE 3-AMINO-6-PHENYLPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES [J].

BERNSTEIN, PR ;

ANDISIK, D ;

BRADLEY, PK ;

BRYANT, CB ;

CECCARELLI, C ;

DAMEWOOD, JR ;

EARLEY, R ;

EDWARDS, PD ;

FEENEY, S ;

GOMES, BC ;

KOSMIDER, BJ ;

STEELMAN, GB ;

THOMAS, RM ;

VACEK, EP ;

VEALE, CA ;

WILLIAMS, JC ;

WOLANIN, DJ ;

WOOLSON, SA .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (20) :3313-3326

[5]

BERNSTEIN PR, IN PRESS J MED CHEM

[6] INHIBITION OF CHYMOTRYPSIN BY PEPTIDYL TRIFLUOROMETHYL KETONES - DETERMINANTS OF SLOW-BINDING KINETICS [J].

BRADY, K ;

ABELES, RH .

BIOCHEMISTRY, 1990, 29 (33) :7608-7617

[7] DESIGN OF ORALLY-ACTIVE, NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE [J].

BROWN, FJ ;

ANDISIK, DW ;

BERNSTEIN, PR ;

BRYANT, CB ;

CECCARELLI, C ;

DAMEWOOD, JR ;

WOOLSON, SA ;

EDWARDS, PD ;

EARLEY, RA ;

FEENEY, S ;

GREEN, RC ;

GOMES, B ;

KOSMIDER, BJ ;

KRELL, RD ;

SHAW, A ;

STEELMAN, GB ;

THOMAS, RN ;

VACEK, EP ;

VEALE, CA ;

TUTHILL, PA ;

WARNER, P ;

WILLIAMS, JC ;

WOLANIN, DJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (09) :1259-1261

[8] NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .2. DESIGN, SYNTHESIS, AND IN-VITRO ACTIVITY OF A SERIES OF 3-AMINO-6-ARYLOPYRIDIN-2-ONE TRIFLUOROMETHYL KETONES [J].

DAMEWOOD, JR ;

EDWARDS, PD ;

FEENEY, S ;

GOMES, BC ;

STEELMAN, GB ;

TUTHILL, PA ;

WILIIAMS, JC ;

WARNER, P ;

WOOLSON, SA ;

WOLANIN, DJ ;

VEALE, CA .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (20) :3303-3312

[9] SYNTHETIC INHIBITORS OF ELASTASE [J].

EDWARDS, PD ;

BERNSTEIN, PR .

MEDICINAL RESEARCH REVIEWS, 1994, 14 (02) :127-194

[10]

MUMFORD RA, 1991, SEP KIN 91 MUN

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