Constrained 7-fluorocarboxychromone-4-aminopiperidine based Melanin-concentrating hormone receptor 1 antagonists: the effects of chirality on substituted indan-1-ylamines.
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
Souers
Andrew J
AJ
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.souers@abbott.com
Iyengar
Rajesh R
RR
Judd
Andrew S
AS
Beno
David W A
DW
Gao
Ju
J
Zhao
Gang
G
Brune
Michael E
ME
Napier
James J
JJ
Mulhern
Mathew M
MM
Lynch
John K
JK
Freeman
Jennifer C
JC
Wodka
Dariusz
D
Chen
Chong J
CJ
Falls
H Doug
HD
Brodjian
Sevan
S
Dayton
Brian D
BD
Diaz
Gilbert J
GJ
Bush
Eugene N
EN
Shapiro
Robin
R
Droz
Brian A
BA
Knourek-Segel
Victoria
V
Hernandez
Lisa E
LE
Marsh
Kennan C
KC
Reilly
Regina M
RM
Sham
Hing L
HL
Collins
Christine A
CA
Kym
Philip R
PR
D000818:Animals; D019440:Anti-Obesity Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001067:Appetite Depressants / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002867:Chromones / Q000138:chemical synthesis* / Q000494:pharmacology*; D004032:Diet; D004041:Dietary Fats; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D005277:Fenfluramine / Q000494:pharmacology; D007202:Indicators and Reagents; D051379:Mice; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000138:chemical synthesis / Q000494:pharmacology; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C518721:7-fluorocarboxychromone-4-aminopiperidine; D019440:Anti-Obesity Agents; D001067:Appetite Depressants; D002867:Chromones; D004041:Dietary Fats; D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; C491209:Mchr1 protein, mouse; D010880:Piperidines; D026902:Potassium Channel Blockers; D017481:Receptors, Somatostatin; D005277:Fenfluramine