The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists

被引：6

作者：

Bell, Ian M. ^{[1
]}

Bednar, Rodney A. ^{[1
]}

Corcoran, Halea A. ^{[3
]}

Fay, John F. ^{[1
]}

Gallicchio, Steven N. ^{[1
]}

Johnston, Victor K. ^{[2
]}

Hershey, James C. ^{[3
]}

Miller-Stein, Cynthia M. ^{[4
]}

Moore, Eric L. ^{[2
]}

Mosser, Scott D. ^{[1
]}

Roller, Shane A. ^{[4
]}

Salvatore, Christopher A. ^{[2
]}

Theberge, Cory R. ^{[1
]}

Wong, Bradley K. ^{[4
]}

Zartman, C. Blair ^{[1
]}

Kane, Stefanie A. ^{[2
]}

Williams, Theresa M. ^{[1
]}

Graham, Samuel L. ^{[1
]}

Vacca, Joseph P. ^{[1
]}

机构：

[1] Merck Res Labs, Dept Med Chem, West Point, PA 19486 USA

[2] Merck Res Labs, Dept Pain Res, West Point, PA 19486 USA

[3] Merck Res Labs, Dept Bone Resp Immunol & Endocrine, West Point, PA 19486 USA

[4] Merck Res Labs, Dept Drug Metab, West Point, PA 19486 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 16期

关键词：

CGRP receptor antagonists; CGRP; Migraine; Orally bioavailable; MIGRAINE; MK-0974; DISCOVERY;

D O I：

10.1016/j.bmcl.2009.06.057

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of tricyclic CGRP receptor antagonists was optimized in order to improve oral bioavailability. Attenuation of polar surface area and incorporation of a weakly basic indoline nitrogen led to compound 5, a potent antagonist with good oral bioavailability in three species. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：4740 / 4742

页数：3

共 15 条

[1] Identification of novel, orally bioavailable spirohydantoin CGRP receptor antagonists [J].

Bell, Ian M. ;

Bednar, Rodney A. ;

Fay, John F. ;

Gallicchio, Steven N. ;

Hochman, Jerome H. ;

McMasters, Daniel R. ;

Miller-Stein, Cynthia ;

Moore, Eric L. ;

Mosser, Scott D. ;

Pudvah, Nicole T. ;

Quigley, Amy G. ;

Salvatore, Christopher A. ;

Stump, Craig A. ;

Theberge, Cory R. ;

Wong, Bradley K. ;

Zartman, C. Blair ;

Zhang, Xu-Fang ;

Kane, Stefanie A. ;

Graham, Samuel L. ;

Vacca, Joseph P. ;

Williams, Theresa M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (24) :6165-6169

[2]

BELL IM, 2006, Patent No. 031491

[3] Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 1. Prediction of intestinal absorption [J].

Clark, DE .

JOURNAL OF PHARMACEUTICAL SCIENCES, 1999, 88 (08) :807-814

[4] VILSMEIER FORMYLATION AND GLYOXYLATION REACTIONS OF NUCLEOPHILIC AROMATIC-COMPOUNDS USING PYROPHOSPHORYL CHLORIDE [J].

DOWNIE, IM ;

EARLE, MJ ;

HEANEY, H ;

SHUHAIBAR, KF .

TETRAHEDRON, 1993, 49 (19) :4015-4034

[5] Calcitonin gene-related peptide antagonists as treatments of migraine and other primary headaches [J].

Goadsby, PJ .

DRUGS, 2005, 65 (18) :2557-2567

[6]

GOADSBY PJ, 2002, LANCET, V346, P257

[7] Investigation of the species selectivity of a nonpeptide CGRP receptor antagonist using a novel pharmacodynamic assay [J].

Hershey, JC ;

Corcoran, HA ;

Baskin, EP ;

Salvatore, CA ;

Mosser, S ;

Williams, TM ;

Koblan, KS ;

Hargreaves, RJ ;

Kane, SA .

REGULATORY PEPTIDES, 2005, 127 (1-3) :71-77

[8] Randomized controlled trial of an oral CGRP receptor antagonist, MK-0974, in acute treatment of migraine [J].

Ho, T. W. ;

Mannix, L. K. ;

Fan, X. ;

Assaid, C. ;

Furtek, C. ;

Jones, C. J. ;

Lines, C. R. ;

Rapoport, A. M. .

NEUROLOGY, 2008, 70 (16) :1304-1312

[9] Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial [J].

Ho, Tony W. ;

Ferrari, Michel D. ;

Dodick, David W. ;

Galet, Vince ;

Kost, James ;

Fan, Xiaoyin ;

Leibensperger, Heather ;

Froman, Samar ;

Assaid, Christopher ;

Lines, Christopher ;

Koppen, Hille ;

Winner, Paul K. .

LANCET, 2008, 372 (9656) :2115-2123

[10] Calcitonin gene-related peptide receptor antagonist BIBN4096BS for the acute treatment of migraine [J].

Olesen, J ;

Diener, H ;

Husstedt, IW ;

Goadsby, PJ ;

Hall, D ;

Meier, U ;

Pollentier, S ;

Lesko, LM .

NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (11) :1104-1110

← 1 2 →