Privileged structure based ligands for melanocortin receptors--4,4-disubstituted piperidine derivatives.
Homologation and cyclization back to the chiral methine of compound 3 yields achiral 4,4-disubstituted piperidine privileged structures (e.g., 8a) useful in the construction of melanocortin 4 receptor (MC4R) ligands. The piperidine nitrogen was replaced with carbon, oxygen, sulfur, and sulfone with minor erosion of binding. The methyl cyclohexane substituent was the most potent while significant affinity was still seen for smaller lipophilic groups such as ethyl.
Kuklish
Steven L
SL
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46258, USA. Kuklish_steven@lilly.com
Backer
Ryan T
RT
Briner
Karin
K
Doecke
Christopher W
CW
Husain
Saba
S
Mullaney
Jeffrey T
JT
Ornstein
Paul L
PL
Zgombick
John M
JM
O'Brien
Thomas P
TP
Fisher
Matthew J
MJ
D001665:Binding Sites; D002244:Carbon / Q000737:chemistry; D003510:Cyclohexanes / Q000737:chemistry; D008024:Ligands; D010100:Oxygen / Q000737:chemistry; D010879:Piperazines / Q000138:chemical synthesis* / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000737:chemistry; D013455:Sulfur / Q000737:chemistry
D003510:Cyclohexanes; D008024:Ligands; D010879:Piperazines; D044105:Receptor, Melanocortin, Type 4; D013450:Sulfones; D013455:Sulfur; D002244:Carbon; D010100:Oxygen