Structural analysis and optimization of NK(1) receptor antagonists through modulation of atropisomer interconversion properties.
We have previously described a series of antagonists that showed high potency and selectivity for the NK(1) receptor. However, these compounds also had the undesirable property of existing as a mixture of interconverting rotational isomers. Here we show that alteration of the 2-naphthyl substituent can modulate the rate of isomer exchange. Comparisons of the NK(1) receptor affinity for the various conformational forms has facilitated the development of a detailed NK(1) pharmacophore model.
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
Ohnmacht
Cyrus
C
Bernstein
Peter R
PR
Rumsey
William L
WL
Aharony
David
D
Alelyunas
Yun
Y
Russell
Daniel J
DJ
Potts
William
W
Sherwood
Scott A
SA
Shen
Lihong
L
Dedinas
Robert F
RF
Palmer
William E
WE
Russell
Keith
K
D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D004285:Dogs; D005849:Gerbillinae; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D009281:Naphthalenes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1