Design, synthesis, and SAR of tachykinin antagonists: modulation of balance in NK(1)/NK(2) receptor antagonist activity.
Through optimization of compounds based on the dual NK(1)/NK(2) antagonist ZD6021, it was found that alteration of two key regions could modulate the balance of NK(1) and NK(2) potency. Substitution of the 2-naphthalene position in analogues of ZD6021 resulted in increased NK(1) potency and thus afforded NK(1) preferential antagonists. Alterations of the piperidine region could then increase NK(2) potency to restore dual NK(1)/NK(2) selectivity. Through these efforts, three novel receptor antagonists from a single chemically related series were identified; two are dual NK(1)/NK(2) antagonists, and the third is an NK(1) preferential antagonist. In this paper, the factors affecting the balance of NK(1) and NK(2) selectivity in this series are discussed and the in vitro and in vivo properties of the novel antagonists are described.
Albert
Jeffrey S
JS
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, P.O. Box 15437, Wilmington, Delaware 19850-5437, USA. jeffrey.albert@astrazeneca.com
Aharony
David
D
Andisik
Donald
D
Barthlow
Herbert
H
Bernstein
Peter R
PR
Bialecki
Russell A
RA
Dedinas
Robert
R
Dembofsky
Bruce T
BT
Hill
Daniel
D
Kirkland
Karin
K
Koether
Gerard M
GM
Kosmider
Benedict J
BJ
Ohnmacht
Cyrus
C
Palmer
William
W
Potts
William
W
Rumsey
William
W
Shen
Lihong
L
Shenvi
Ashok
A
Sherwood
Scott
S
Warwick
Paul J
PJ
Russell
Keith
K
D000818:Animals; D001682:Biological Availability; D004285:Dogs; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018041:Receptors, Neurokinin-2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013454:Sulfoxides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D015320:Tachykinins / Q000037:antagonists & inhibitors*
C465464:N-(2-(3,4-dichlorophenyl)-4-(4-(2-methylsulfinylphenyl)-1-piperdinyl)butyl)-N-methyl-2-methoxy-3-cyano-1-naphthamide; C465465:N-(2-(3,4-dichlorophenyl)-4-(4-(2-oxo-1-piperidinyl)-4-(N-methylaminocarbonyl)-1-piperidinyl)butyl)-N-methyl-3-cyano-2-methoxy-1-naphthamide; C465463:N-(2-(3,4-dichlorophenyl)-4-(4-(4-methoxy-2-methylsulfinylphenyl)-1-piperidinyl)butyl)-N-methyl-3-cyano-1-naphthamide; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D018041:Receptors, Neurokinin-2; D013454:Sulfoxides; D015320:Tachykinins