title: Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist.
abstract: This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.
authors: Pfizer Global Research and Development, Cambridge University Forvie Site, Robinson Way, Cambridge CB2 2QB, UK.
authors: V A
authors: VA
authors: Ashwood
authors: M J
authors: MJ
authors: Field
authors: D C
authors: DC
authors: Horwell
authors: C
authors: C
authors: Julien-Larose
authors: R A
authors: RA
authors: Lewthwaite
authors: S
authors: S
authors: McCleary
authors: M C
authors: MC
authors: Pritchard
authors: J
authors: J
authors: Raphy
authors: L
authors: L
authors: Singh
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001921:Brain / Q000378:metabolism*; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018360:Crystallography, X-Ray; D005849:Gerbillinae; D006614:Hindlimb; D006801:Humans; D006860:Hydrogen Bonding; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007276:Injections, Intraventricular; D007279:Injections, Subcutaneous; D008958:Models, Molecular; D064729:Neurokinin-1 Receptor Antagonists; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D001572:Benzofurans; C112778:CI 1021; D002219:Carbamates; D007211:Indoles; D064729:Neurokinin-1 Receptor Antagonists; C430897:PD 174424; D018040:Receptors, Neurokinin-1; D013373:Substance P