title: 4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity.
abstract: Previously reported studies from these laboratories described the design of a novel series of high-affinity NK1 antagonists based on the 4,4-disubstituted piperidine ring system. Further structure-activity studies have now established that for high NK1 affinity the benzyl ether side chain must be 3,5-disubstituted and highly lipophilic, the optimal side chain being the 3, 5-bis(trifluoromethyl)benzyl ether, 12 (hNK1 IC50 = 0.95 nM). Additional studies have shown that this class of NK1 antagonist tolerates a wider range of substituents on the piperidine nitrogen, including acyl (38) (hNK1 IC50 = 5.3 nM) and sulfonyl (39) (hNK1 IC50 = 5.7 nM) derivatives. Following preliminary pharmacokinetic analysis, two compounds (32 and 43) were selected for in vivo study in the resiniferotoxin-induced vascular leakage model, both showing excellent profiles (ID50 = 0.22 and 0.28 mg/kg, respectively).
authors.affiliation: Department of Medicinal Chemistry, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
authors.forename: G I
authors.initials: GI
authors.lastname: Stevenson
authors.forename: I
authors.initials: I
authors.lastname: Huscroft
authors.forename: A M
authors.initials: AM
authors.lastname: MacLeod
authors.forename: C J
authors.initials: CJ
authors.lastname: Swain
authors.forename: M A
authors.initials: MA
authors.lastname: Cascieri
authors.forename: G G
authors.initials: GG
authors.lastname: Chicchi
authors.forename: M I
authors.initials: MI
authors.lastname: Graham
authors.forename: T
authors.initials: T
authors.lastname: Harrison
authors.forename: F J
authors.initials: FJ
authors.lastname: Kelleher
authors.forename: M
authors.initials: M
authors.lastname: Kurtz
authors.forename: T
authors.initials: T
authors.lastname: Ladduwahetty
authors.forename: K J
authors.initials: KJ
authors.lastname: Merchant
authors.forename: J M
authors.initials: JM
authors.lastname: Metzger
authors.forename: D E
authors.initials: DE
authors.lastname: MacIntyre
authors.forename: S
authors.initials: S
authors.lastname: Sadowski
authors.forename: B
authors.initials: B
authors.lastname: Sohal
authors.forename: A P
authors.initials: AP
authors.lastname: Owens
mesh_terms: D000818:Animals; D016466:CHO Cells; D002199:Capillary Permeability / Q000187:drug effects; D006224:Cricetinae; D004224:Diterpenes / Q000633:toxicity; D004947:Esophagus / Q000098:blood supply / Q000187:drug effects; D006168:Guinea Pigs; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D018040:Receptors, Neurokinin-1 / Q000096:biosynthesis; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics
chemical_list: C115591:1-(4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-phenylpiperidin-1-yl)-2-pyrrolidineacetamide; C115592:4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-1-(2-methylthiazol-5-ylmethyl)-4-phenylpiperidine; D004224:Diterpenes; D007295:Inositol Phosphates; D064729:Neurokinin-1 Receptor Antagonists; D010880:Piperidines; D011759:Pyrrolidines; D018040:Receptors, Neurokinin-1; D013844:Thiazoles; C024353:resiniferatoxin