title: Structural analysis and optimization of NK(1) receptor antagonists through modulation of atropisomer interconversion properties.
abstract: 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.
authors.affiliation: CNS Discovery Research, AstraZeneca Pharmaceuticals LP, 1800 Concord Pike, P.O. Box 15437, Wilmington, Delaware 19850-5437, USA. jeffrey.albert@astrazeneca.com
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Albert
authors.forename: Cyrus
authors.initials: C
authors.lastname: Ohnmacht
authors.forename: Peter R
authors.initials: PR
authors.lastname: Bernstein
authors.forename: William L
authors.initials: WL
authors.lastname: Rumsey
authors.forename: David
authors.initials: D
authors.lastname: Aharony
authors.forename: Yun
authors.initials: Y
authors.lastname: Alelyunas
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Russell
authors.forename: William
authors.initials: W
authors.lastname: Potts
authors.forename: Scott A
authors.initials: SA
authors.lastname: Sherwood
authors.forename: Lihong
authors.initials: L
authors.lastname: Shen
authors.forename: Robert F
authors.initials: RF
authors.lastname: Dedinas
authors.forename: William E
authors.initials: WE
authors.lastname: Palmer
authors.forename: Keith
authors.initials: K
authors.lastname: Russell
mesh_terms: 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
chemical_list: D009281:Naphthalenes; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1