Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates

被引：99

作者：

Sanderson, PEJ ^{[1
]}

Lyle, TA

Cutrona, KJ

Dyer, DL

Dorsey, BD

McDonough, CM

Naylor-Olsen, AM

Chen, IW

Chen, ZG

Cook, JJ

Cooper, CM

Gardell, SJ

Hare, TR

Krueger, JA

Lewis, SD

Lin, JH

Lucas, BJ

Lyle, EA

Lynch, JJ

Stranieri, MT

Vastag, K

Yan, YW

Shafer, JA

Vacca, JP

机构：

[1] Merck Res Labs, Dept Antiviral Res, W Point, PA 19486 USA

[2] Merck Res Labs, Dept Biol Chem, W Point, PA 19486 USA

[3] Merck Res Labs, Dept Drug Metab, W Point, PA 19486 USA

[4] Merck Res Labs, Dept Med Chem, W Point, PA 19486 USA

[5] Merck Res Labs, Dept Mol Design & Divers, W Point, PA 19486 USA

[6] Merck Res Labs, Dept Pharmacol, W Point, PA 19486 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 1998年 / 41卷 / 23期

关键词：

D O I：

10.1021/jm980368v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.

引用

页码：4466 / 4474

页数：9

共 21 条

[1] Discovery and development of the novel potent orally active thrombin inhibitor N-(9-hydroxy-9-fluorenecarboxy)prolyl trans-4-aminocyclohexylmethyl amide (L-372,460):: Coapplication of structure-based design and rapid multiple analogue synthesis on solid support [J].

Brady, SF ;

Stauffer, KJ ;

Lumma, WC ;

Smith, GM ;

Ramjit, HG ;

Lewis, SD ;

Lucas, BJ ;

Gardell, SJ ;

Lyle, EA ;

Appleby, SD ;

Cook, JJ ;

Holahan, MA ;

Stranieri, MT ;

Lynch, JJ ;

Lin, JH ;

Chen, IW ;

Vastag, K ;

Naylor-Olsen, AM ;

Vacca, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1998, 41 (03) :401-406

[2] 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

[3] A GREATLY IMPROVED PROCEDURE FOR RUTHENIUM TETRAOXIDE CATALYZED OXIDATIONS OF ORGANIC-COMPOUNDS [J].

CARLSEN, PHJ ;

KATSUKI, T ;

MARTIN, VS ;

SHARPLESS, KB .

JOURNAL OF ORGANIC CHEMISTRY, 1981, 46 (19) :3936-3938

[4] Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog [J].

Cousins, GR ;

Friedrichs, GS ;

Sudo, Y ;

Rebello, SS ;

Rote, WE ;

Vlasuk, GP ;

Nolan, TG ;

Mendoza, C ;

Lucchesi, BR .

CIRCULATION, 1996, 94 (07) :1705-1712

[5] Antithrombotic agents and thromboembolic disease [J].

Ewenstein, BM .

NEW ENGLAND JOURNAL OF MEDICINE, 1997, 337 (19) :1383-1384

[6] Discovery of a novel, selective, and orally bioavailable class of thrombin inhibitors incorporating aminopyridyl moieties at the P1 position [J].

Feng, DM ;

Gardell, SJ ;

Lewis, SD ;

Bock, MG ;

Chen, ZG ;

Freidinger, RM ;

NaylorOlsen, AM ;

Ramjit, HG ;

Woltmann, R ;

Baskin, EP ;

Lynch, JJ ;

Lucas, R ;

Shafer, JA ;

Dancheck, KB ;

Chen, IW ;

Mao, SS ;

Krueger, JA ;

Hare, TR ;

Mulichak, AM ;

Vacca, JP .

JOURNAL OF MEDICINAL CHEMISTRY, 1997, 40 (23) :3726-3733

[7]

Gustafsson D, 1998, THROMB HAEMOSTASIS, V79, P110

[8] DESIGN AND SYNTHESIS OF POTENT AND HIGHLY SELECTIVE THROMBIN INHIBITORS [J].

HILPERT, K ;

ACKERMANN, J ;

BANNER, DW ;

GAST, A ;

GUBERNATOR, K ;

HADVARY, P ;

LABLER, L ;

MULLER, K ;

SCHMID, G ;

TSCHOPP, TB ;

VANDEWATERBEEMD, H .

JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (23) :3889-3901

[9] RAT MODEL OF ARTERIAL THROMBOSIS INDUCED BY FERRIC-CHLORIDE [J].

KURZ, KD ;

MAIN, BW ;

SANDUSKY, GE .

THROMBOSIS RESEARCH, 1990, 60 (04) :269-280

[10] SYNTHESIS OF ALPHA-AMINONITRILES BY SELF-CATALYZED, STOICHIOMETRIC REACTION OF PRIMARY AMINES, ALDEHYDES, AND TRIMETHYLSILYL CYANIDE [J].

LEBLANC, JP ;

GIBSON, HW .

TETRAHEDRON LETTERS, 1992, 33 (42) :6295-6298

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