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Discovery of novel, orally active dual NK1/NK2 antagonists
- Source :
- Bioorganic & Medicinal Chemistry Letters. 11:2769-2773
- Publication Year :
- 2001
- Publisher :
- Elsevier BV, 2001.
-
Abstract
- Exploration of the SAR around selective NK 2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK 1 and NK 2 antagonists. ZD6021 inhibited binding of [ 3 H]-NKA or [ 3 H]-SP to human NK 1 and NK 2 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 p K B =8.9 and in human bronchus p K B =7.3, for NK 1 and NK 2 , respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED 50 =0.5 mg/kg, and NK 2 mediated bronchoconstriction, ED 50 =13 mg/kg.
- Subjects :
- Guinea Pigs
Clinical Biochemistry
Administration, Oral
Pharmaceutical Science
Pharmacology
Biochemistry
Guinea pig
Structure-Activity Relationship
Dogs
Neurokinin-1 Receptor Antagonists
Piperidines
In vivo
Oral administration
Drug Discovery
Animals
Receptor
Molecular Biology
Dose-Response Relationship, Drug
Chemistry
Organic Chemistry
Antagonist
Receptors, Neurokinin-2
In vitro
Extravasation
Rats
Sulfoxides
Benzamides
Models, Animal
Molecular Medicine
Tachykinin receptor
Subjects
Details
- ISSN :
- 0960894X
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry Letters
- Accession number :
- edsair.doi.dedup.....885131fda56c66af522cb021237bb06a