4,4-Disubstituted piperidine high-affinity NK1 antagonists: structure-activity relationships and in vivo activity.
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).
Stevenson
G I
GI
Department of Medicinal Chemistry, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK.
Huscroft
I
I
MacLeod
A M
AM
Swain
C J
CJ
Cascieri
M A
MA
Chicchi
G G
GG
Graham
M I
MI
Harrison
T
T
Kelleher
F J
FJ
Kurtz
M
M
Ladduwahetty
T
T
Merchant
K J
KJ
Metzger
J M
JM
MacIntyre
D E
DE
Sadowski
S
S
Sohal
B
B
Owens
A P
AP
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
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