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Discovery of novel, orally active dual NK1/NK2 antagonists.

Abstract：

: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 [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (K(i)=0.12 and 0.62nM, 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, ED(50)=0.5mg/kg, and NK2 mediated bronchoconstriction, ED(50)=13mg/kg.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Bernstein PR,Aharony D,Albert JS,Andisik D,Barthlow HG,Bialecki R,Davenport T,Dedinas RF,Dembofsky BT,Koether G,Kosmider BJ,Kirkland K,Ohnmacht CJ,Potts W,Rumsey WL,Shen L,Shenvi A,Sherwood S,Stollman D,Russell K

doi

10.1016/s0960-894x(01)00572-8

subject

Has Abstract

pub_date

2001-10-22 00:00:00

pages

2769-73

issue

20

eissn

0960-894X

issn

1464-3405

pii

S0960894X01005728

journal_volume

11

pub_type

杂志文章

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