Discovery of novel, orally active dual NK1/NK2 antagonists

被引：38

作者：

Bernstein, PR ^{[1
]}

Aharony, D ^{[1
]}

Albert, JS ^{[1
]}

Andisik, D ^{[1
]}

Barthlow, HG ^{[1
]}

Bialecki, R ^{[1
]}

Davenport, T ^{[1
]}

Dedinas, RF ^{[1
]}

Dembofsky, BT ^{[1
]}

Koether, G ^{[1
]}

Kosmider, BJ ^{[1
]}

Kirkland, K ^{[1
]}

Ohnmacht, CJ ^{[1
]}

Potts, W ^{[1
]}

Rumsey, WL ^{[1
]}

Shen, LH ^{[1
]}

Shenvi, A ^{[1
]}

Sherwood, S ^{[1
]}

Stollman, D ^{[1
]}

Russell, K ^{[1
]}

机构：

[1] AstraZeneca Pharmaceut LP, CNS Discovery Res, Wilmington, DE 19850 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2001年 / 11卷 / 20期

关键词：

D O I：

10.1016/S0960-894X(01)00572-8

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [H-3]-NKA or [H-3]-SP to human NK1 and NK2 receptors, with high-affinity (K-i = 0. 12 and 0.62 nM, respectively). In functional assays ZD6021 had, at 10-7 M, in human pulmonary artery pK(B) = 8.9 and in human bronchus pK(B) = 7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED50 = 0.5 mg/kg, and NK2 mediated bronchoconstriction, ED50 = 13 mg/kg. (C) 2001 Elsevier Science Ltd. All rights reserved.

引用

页码：2769 / 2773

页数：5

共 17 条

[1] SUBSTITUENT EFFECTS .8. SYNTHESIS OF SUBSTITUTED ALPHA- AND BETA-FLUORONAPHTHALENS [J].

ADCOCK, W ;

DEWAR, MJS .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1967, 89 (02) :386-&

[2]

Advenier C, 1999, CLIN EXP ALLERGY, V29, P579

[3]

AHARONY D, 1995, J PHARMACOL EXP THER, V274, P1216

[4] NEUROPEPTIDES IN THE RESPIRATORY-TRACT .1. [J].

BARNES, PJ ;

BARANIUK, JN ;

BELVISI, MG .

AMERICAN REVIEW OF RESPIRATORY DISEASE, 1991, 144 (05) :1187-1198

[5] REGIOSELECTIVE MONOMETHYLATION OF UNSYMMETRICAL NAPHTHALENEDIOLS WITH METHANOLIC HCL [J].

BELL, KH ;

MCCAFFERY, LF .

AUSTRALIAN JOURNAL OF CHEMISTRY, 1993, 46 (05) :731-737

[6]

BUCKNER CK, 1993, J PHARMACOL EXP THER, V267, P1168

[7] Identification and chemical synthesis of MDL 105,212, a non-peptide tachykinin antagonist with high affinity for NK1 and NK2 receptors. [J].

Burkholder, TP ;

Kudlacz, EM ;

Le, TB ;

Knippenberg, RW ;

Shatzer, SA ;

Maynard, GD ;

Webster, ME ;

Horgan, SW .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 1996, 6 (08) :951-956

[8]

EMONDSALT X, 1992, LIFE SCI, V50, P101

[9]

Gao ZL, 1999, CURR MED CHEM, V6, P375

[10]

Gerspacher Marc, 1999, Drugs of the Future, V24, P883, DOI 10.1358/dof.1999.024.08.858627

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