Identification of pharmacokinetically stable 3,10-dibromo-8-chlorobenzocycloheptapyridine farnesyl protein transferase inhibitors with potent enzyme and cellular activities

被引：22

作者：

Taveras, AG ^{[1
]}

Deskus, J ^{[1
]}

Chao, JP ^{[1
]}

Vaccaro, CJ ^{[1
]}

Njoroge, FG ^{[1
]}

Vibulbhan, B ^{[1
]}

Pinto, P ^{[1
]}

Remiszewski, S ^{[1
]}

del Rosario, J ^{[1
]}

Doll, RJ ^{[1
]}

Alvarez, C ^{[1
]}

Lalwani, T ^{[1
]}

Mallams, AK ^{[1
]}

Rossman, RR ^{[1
]}

Afonso, A ^{[1
]}

Girijavallabhan, VM ^{[1
]}

Ganguly, AK ^{[1
]}

Pramanik, B ^{[1
]}

Heimark, L ^{[1
]}

Bishop, WR ^{[1
]}

Wang, L ^{[1
]}

Kirschmeier, P ^{[1
]}

James, L ^{[1
]}

Carr, D ^{[1
]}

Patton, R ^{[1
]}

Bryant, MS ^{[1
]}

Nomeir, AA ^{[1
]}

Liu, M ^{[1
]}

机构：

[1] Schering Plough Res Inst, Anti Infect & Tumor Biol Res, Kenilworth, NJ 07033 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1999年 / 42卷 / 14期

关键词：

D O I：

10.1021/jm990059k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

引用

页码：2651 / 2661

页数：11

共 32 条

[1] HYDRAZINSULFONSAURE-AMIDE .1. UBER DAS HYDRAZODISULFAMID [J].

APPEL, R ;

BERGER, G .

CHEMISCHE BERICHTE-RECUEIL, 1958, 91 (06) :1339-1341

[2] N-SULFONYLAMINES [J].

ATKINS, GM ;

BURGESS, EM .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1967, 89 (10) :2502-&

[3] RAS GENES [J].

BARBACID, M .

ANNUAL REVIEW OF BIOCHEMISTRY, 1987, 56 :779-827

[4] RAS ONCOGENES - THEIR ROLE IN NEOPLASIA [J].

BARBACID, M .

EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, 1990, 20 (03) :225-235

[5] Novel tricyclic inhibitors of farnesyl protein transferase - Biochemical characterization and inhibition of Ras modification in transfected Cos cells [J].

Bishop, WR ;

Bond, R ;

Petrin, J ;

Wang, L ;

Patton, R ;

Doll, R ;

Njoroge, G ;

Catino, J ;

Schwartz, J ;

Windsor, W ;

Syto, R ;

Schwartz, J ;

Carr, D ;

James, L ;

Kirschmeier, P .

JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (51) :30611-30618

[6] Pharmacokinetic screening for the selection of new drug discovery candidates is greatly enhanced through the use of liquid chromatography atmospheric pressure ionization tandem mass spectrometry [J].

Bryant, MS ;

Korfmacher, WA ;

Wang, SY ;

Nardo, C ;

Nomeir, AA ;

Lin, CC .

JOURNAL OF CHROMATOGRAPHY A, 1997, 777 (01) :61-66

[7] P21RAS IS MODIFIED BY A FARNESYL ISOPRENOID [J].

CASEY, PJ ;

SOLSKI, PA ;

DER, CJ ;

BUSS, JE .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (21) :8323-8327

[8]

COPPA F, 1993, HETEROCYCLES, V36, P2687

[9]

DER CJ, 1991, CANCER CELL-MON REV, V3, P331

[10]

GARCIA AM, 1993, J BIOL CHEM, V268, P18415

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