Design, Synthesis, and SAR of Tachykinin Antagonists:  Modulation of Balance in NK1/NK2 Receptor Antagonist Activity

Through optimization of compounds based on the dual NK1/NK2 antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK1 and NK2 potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK1 potency and thus afforded NK1...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2002-08, Vol.45 (18), p.3972-3983
Main Authors: Albert, Jeffrey S, Aharony, David, Andisik, Donald, Barthlow, Herbert, Bernstein, Peter R, Bialecki, Russell A, Dedinas, Robert, Dembofsky, Bruce T, Hill, Daniel, Kirkland, Karin, Koether, Gerard M, Kosmider, Benedict J, Ohnmacht, Cyrus, Palmer, William, Potts, William, Rumsey, William, Shen, Lihong, Shenvi, Ashok, Sherwood, Scott, Warwick, Paul J, Russell, Keith
Format: Article
Language:English
Subjects:
Biological and medical sciences
Medical sciences
Pharmacology. Drug treatments
Respiratory system
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Summary:Through optimization of compounds based on the dual NK1/NK2 antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK1 and NK2 potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK1 potency and thus afforded NK1 preferential antagonists. Alterations of the piperidine region could then increase NK2 potency to restore dual NK1/NK2 selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK1/NK2 antagonists, and the third is an NK1 preferential antagonist. In this paper, the factors affecting the balance of NK1 and NK2 selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm020094i