Discovery of novel, orally active dual NK1/NK2 antagonists

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, respe...

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Published in:Bioorganic & medicinal chemistry letters 2001-10, Vol.11 (20), p.2769-2773
Main Authors: BERNSTEIN, Peter R, AHARONY, David, KOSMIDER, Benedict J, KIRKLAND, Karin, OHNMACHT, Cyrus J, POTTS, William, RUMSEY, William L, LIHONG SHEN, SHENVI, Ashok, SHERWOOD, Scott, STOLLMAN, David, RUSSELL, Keith, ALBERT, Jeffrey S, ANDISIK, Donald, BARTHLOW, Herbert G, BIALECKI, Russell, DAVENPORT, Timothy, DEDINAS, Robert F, DEMBOFSKY, Bruce T, KOETHER, Gerard
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Benzamides - chemistry
Benzamides - pharmacokinetics
Benzamides - pharmacology
Biological and medical sciences
Dogs
Dose-Response Relationship, Drug
Guinea Pigs
Medical sciences
Models, Animal
Neurokinin-1 Receptor Antagonists
Pharmacology. Drug treatments
Piperidines - chemistry
Piperidines - pharmacokinetics
Piperidines - pharmacology
Rats
Receptors, Neurokinin-2 - antagonists & inhibitors
Respiratory system
Structure-Activity Relationship
Sulfoxides - chemistry
Sulfoxides - pharmacokinetics
Sulfoxides - pharmacology
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Summary: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.
ISSN:0960-894X
1464-3405
DOI:10.1016/s0960-894x(01)00572-8