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.
CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, P.O. Box 15437, Wilmington, Delaware 19850-5437, USA. jeffrey.albert@astrazeneca.com
Jeffrey S
JS
Albert
David
D
Aharony
Donald
D
Andisik
Herbert
H
Barthlow
Peter R
PR
Bernstein
Russell A
RA
Bialecki
Robert
R
Dedinas
Bruce T
BT
Dembofsky
Daniel
D
Hill
Karin
K
Kirkland
Gerard M
GM
Koether
Benedict J
BJ
Kosmider
Cyrus
C
Ohnmacht
William
W
Palmer
William
W
Potts
William
W
Rumsey
Lihong
L
Shen
Ashok
A
Shenvi
Scott
S
Sherwood
Paul J
PJ
Warwick
Keith
K
Russell
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