Discovery and characterization of aminopiperidinecoumarin melanin concentrating hormone receptor 1 antagonists.
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
Kym
Philip R
PR
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. phil.r.kym@abbott.com
Iyengar
Rajesh
R
Souers
Andrew J
AJ
Lynch
John K
JK
Judd
Andrew S
AS
Gao
Ju
J
Freeman
Jennifer
J
Mulhern
Mathew
M
Zhao
Gang
G
Vasudevan
Anil
A
Wodka
Dariusz
D
Blackburn
Christopher
C
Brown
Jim
J
Che
Jennifer Lee
JL
Cullis
Courtney
C
Lai
Su Jen
SJ
LaMarche
Matthew J
MJ
Marsilje
Tom
T
Roses
Jon
J
Sells
Todd
T
Geddes
Brad
B
Govek
Elizabeth
E
Patane
Michael
M
Fry
Dennis
D
Dayton
Brian D
BD
Brodjian
Sevan
S
Falls
Doug
D
Brune
Michael
M
Bush
Eugene
E
Shapiro
Robin
R
Knourek-Segel
Victoria
V
Fey
Thomas
T
McDowell
Cathleen
C
Reinhart
Glenn A
GA
Preusser
Lee C
LC
Marsh
Kennan
K
Hernandez
Lisa
L
Sham
Hing L
HL
Collins
Christine A
CA
D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D004285:Dogs; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009200:Myocardial Contraction / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D019440:Anti-Obesity Agents; D003374:Coumarins; C491209:Mchr1 protein, mouse; D010880:Piperidines; D011979:Receptors, Pituitary Hormone; D017481:Receptors, Somatostatin; C092274:melanin-concentrating hormone receptor