4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity

G I Stevenson; I Huscroft; A M MacLeod; C J Swain; M A Cascieri; G G Chicchi; M I Graham; T Harrison; F J Kelleher; M Kurtz; T Ladduwahetty; K J Merchant; J M Metzger; D E MacIntyre; S Sadowski; B Sohal; A P Owens

doi:10.1021/jm980376b

4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity

J Med Chem. 1998 Nov 5;41(23):4623-35. doi: 10.1021/jm980376b.

Authors

G I Stevenson¹, I Huscroft, A M MacLeod, C J Swain, M A Cascieri, G G Chicchi, M I Graham, T Harrison, F J Kelleher, M Kurtz, T Ladduwahetty, K J Merchant, J M Metzger, D E MacIntyre, S Sadowski, B Sohal, A P Owens

Affiliation

¹ Department of Medicinal Chemistry, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.

PMID: 9804702
DOI: 10.1021/jm980376b

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).

MeSH terms

Animals
CHO Cells
Capillary Permeability / drug effects
Cricetinae
Diterpenes / toxicity
Esophagus / blood supply
Esophagus / drug effects
Guinea Pigs
Inositol Phosphates / metabolism
Male
Neurokinin-1 Receptor Antagonists*
Piperidines / chemical synthesis*
Piperidines / pharmacokinetics
Piperidines / pharmacology
Pyrrolidines / chemical synthesis*
Pyrrolidines / pharmacokinetics
Pyrrolidines / pharmacology
Radioligand Assay
Receptors, Neurokinin-1 / biosynthesis
Structure-Activity Relationship
Thiazoles / chemical synthesis*
Thiazoles / pharmacokinetics

Substances

1-(4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-4-phenylpiperidin-1-yl)-2-pyrrolidineacetamide
4-(3,5-bis(trifluoromethyl)benzyloxymethyl)-1-(2-methylthiazol-5-ylmethyl)-4-phenylpiperidine
Diterpenes
Inositol Phosphates
Neurokinin-1 Receptor Antagonists
Piperidines
Pyrrolidines
Receptors, Neurokinin-1
Thiazoles
resiniferatoxin