Syntheses and biological evaluation of novel quinuclidine derivatives as squalene synthase inhibitors

被引：33

作者：

Ishihara, T ^{[1
]}

Kakuta, H ^{[1
]}

Moritani, H ^{[1
]}

Ugawa, T ^{[1
]}

Sakamoto, S ^{[1
]}

Tsukamoto, S ^{[1
]}

Yanagisawa, I ^{[1
]}

机构：

[1] Yamanouchi Pharmaceut Co Ltd, Inst Drug Disvocery Res, Tsukuba, Ibaraki 3058585, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2003年 / 11卷 / 11期

关键词：

D O I：

10.1016/S0968-0896(03)00143-3

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Squalene synthase (E.C. 2.5.1.21) catalyses the reductive dimerization of two molecules of farnesyl diphosphate to form squalene and is involved in the first committed step in cholesterol biosynthesis. Inhibition of this enzyme is therefore an attractive target for hypocholesterolemic strategies. A series of quinuclidine derivatives incorporating a tricyclic system was synthesized and evaluated for their ability to inhibit squalene synthase in vitro. A 9H-fluorene moiety was found to be optimal as the tricyclic system for potent inhibitory activity. Improved activity can be achieved with a conformation ally constrained three-atom linkage connecting the tricyclic system with the quinuclidine nucleus. Among these compounds, (Z)-3-[2-(9H-fluoren-2-yloxy)ethylidene]-quinuclidine hydrochloride 31 was found to be a potent inhibitor of squalene synthase derived from hamster liver and human hepatoma cells with IC50 values of 76 and 48 nM, respectively. Oral dosing of compound 31 demonstrated effective reduction of plasma non-HDL cholesterol levels in hamsters. (C) 2003 Elsevier Science Ltd. All rights reserved.

引用

页码：2403 / 2414

页数：12

共 57 条

[1] INHIBITORS OF SQUALENE BIOSYNTHESIS AND METABOLISM [J].

ABE, I ;

TOMESCH, JC ;

WATTANASIN, S ;

PRESTWICH, GD .

NATURAL PRODUCT REPORTS, 1994, 11 (03) :279-302

[2]

Alberts A. W., 1990, DRUG INVEST S2, V2, P9

[3]

AMIN D, 1992, J LIPID RES, V33, P1657

[4]

Biller SA, 1996, CURR PHARM DESIGN, V2, P1

[5] AROMATIC ISOSTERES AS CONFORMATIONAL PROBES FOR AN ISOPRENYL SUBUNIT - APPLICATION TO INHIBITORS OF SQUALENE SYNTHASE [J].

BILLER, SA ;

ABT, JW ;

PUDZIANOWSKI, AT ;

RICH, LC ;

SLUSARCHYK, DA ;

CIOSEK, CP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1993, 3 (04) :595-600

[6] ISOPRENYL PHOSPHINYLFORMATES - NEW INHIBITORS OF SQUALENE SYNTHETASE [J].

BILLER, SA ;

FORSTER, C ;

GORDON, EM ;

HARRITY, T ;

RICH, LC ;

MARRETTA, J ;

CIOSEK, CP .

JOURNAL OF MEDICINAL CHEMISTRY, 1991, 34 (06) :1912-1914

[7] THE 1ST POTENT INHIBITOR OF SQUALENE SYNTHASE - A PROFOUND CONTRIBUTION OF AN ETHER OXYGEN TO INHIBITOR ENZYME INTERACTION [J].

BILLER, SA ;

SOFIA, MJ ;

DELANGE, B ;

FORSTER, C ;

GORDON, EM ;

HARRITY, T ;

RICH, LC ;

CIOSEK, CP .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1991, 113 (22) :8522-8524

[8] Synthesis and activity of a novel series of 3-biarylquinuclidine squalene synthase inhibitors [J].

Brown, GR ;

Clarke, DS ;

Foubister, AJ ;

Freeman, S ;

Harrison, PJ ;

Johnson, MC ;

Mallion, KB ;

McCormick, J ;

McTaggart, F ;

Reid, AC ;

Smith, GJ ;

Taylor, MJ .

JOURNAL OF MEDICINAL CHEMISTRY, 1996, 39 (15) :2971-2979

[9] Novel optimised quinuclidine squalene synthase inhibitors [J].

Brown, GR ;

Foubister, AJ ;

Freeman, S ;

McTaggart, F ;

Mirrlees, DJ ;

Reid, AC ;

Smith, GJ ;

Taylor, MJ ;

Thomason, DA ;

Whittamore, PRO .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1997, 7 (05) :597-600

[10] AN ALDEHYDE OF THE PHENOTHIAZINE SERIES [J].

BUUHOI, NP ;

HOAN, N .

JOURNAL OF THE CHEMICAL SOCIETY, 1951, (JUL) :1834-1836

← 1 2 3 4 5 6 →