title: An orally active, water-soluble neurokinin-1 receptor antagonist suitable for both intravenous and oral clinical administration.
abstract: 1-(5-[[(2R,3S)-2-([(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl]oxy)-3-(4-fluorophenyl)morpholin-4-yl]methyl]-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine hydrochloride 3 is a high affinity, orally active, h-NK(1) receptor antagonist with a long central duration of action and a solubility in water of >100 mg/mL. The construction of the 5-dimethylaminomethyl 1,2,3-triazol-4-yl unit, which incorporates the solubilizing group of 3, was accomplished by thermal rearrangement of a propargylic azide in the presence of dimethylamine. Compound 3 is highly effective in pre-clinical tests that are relevant to clinical efficacy in emesis and depression.
authors.affiliation: The Neuroscience Research Centre, Merck, Sharp & Dohme, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK. timothy_harrison@merck.com
authors.forename: T
authors.initials: T
authors.lastname: Harrison
authors.forename: A P
authors.initials: AP
authors.lastname: Owens
authors.forename: B J
authors.initials: BJ
authors.lastname: Williams
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
authors.forename: A
authors.initials: A
authors.lastname: Williams
authors.forename: E J
authors.initials: EJ
authors.lastname: Carlson
authors.forename: W
authors.initials: W
authors.lastname: Rycroft
authors.forename: F D
authors.initials: FD
authors.lastname: Tattersall
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: N M
authors.initials: NM
authors.lastname: Rupniak
authors.forename: R J
authors.initials: RJ
authors.lastname: Hargreaves
mesh_terms: D000284:Administration, Oral; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D000928:Antidepressive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000932:Antiemetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D005289:Ferrets; D005849:Gerbillinae; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008253:Macaca mulatta; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D064729:Neurokinin-1 Receptor Antagonists; D011869:Radioligand Assay; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014828:Vocalization, Animal / Q000187:drug effects
chemical_list: C440622:1-(5-((2-((1-(3,5-bis(trifluoromethyl)phenyl)ethyl)oxy)-3-(4-fluorophenyl)morpholin-4-yl)methyl)-2H-1,2,3-triazol-4-yl)-N,N-dimethylmethanamine; D000588:Amines; D000928:Antidepressive Agents; D000932:Antiemetics; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D014230:Triazoles