Identification of substituted 4-aminopiperidines and 3-aminopyrrolidines as potent MCH-R1 antagonists for the treatment of obesity.
A substituted 4-aminopiperidine was identified as showing activity in an MCH assay from an HTS effort. Subsequent structural modification of the scaffold led to the identification of a number of active MCH antagonists. 3,5-Dimethoxy-N-(1-(naphthalen-2-ylmethyl)piperidin-4-yl)benzamide (5c) was among those with the highest binding affinity to the MCH receptor (K(i)=27nM), when variations were made at benzoyl and naphthylmethyl substitution sites from the initial HTS hit. Further optimization via piperidine ring contraction resulted in enhanced MCH activity in a 3-aminopyrrolidine series, where (R)-3,5-dimethoxy-N-(1-(naphthalen-2-ylmethyl)-pyrrolidin-3-yl)benzamide (10i) was found to be an excellent MCH antagonist (K(i)=7nM).
Kim
Nick
N
Procter and Gamble Pharmaceuticals, 8700 Mason-Montgomery Road, Mason, OH 45040, USA.
Meyers
Kenneth M
KM
Mendez-Andino
Jose L
JL
Warshakoon
Namal C
NC
Ji
Wei
W
Wos
John A
JA
Colson
Annyodile
A
Mitchell
M Chrissy
MC
Davis
Jan R
JR
Pinney
Beth B
BB
Reizes
Ofer
O
Hu
X Eric
XE
D001667:Binding, Competitive / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D009765:Obesity / Q000188:drug therapy*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C481395:4-aminopiperidine; C103263:MCHR1 protein, human; D010880:Piperidines; D011759:Pyrrolidines; D017481:Receptors, Somatostatin