Identification of diamino chromone-2-carboxamides as MCHr1 antagonists with minimal hERG channel activity.
A series of potent 2-carboxychromone-based melanin-concentrating hormone receptor 1 (MCHr1) antagonists were synthesized and evaluated for hERG (human Ether-a-go-go Related Gene) channel affinity and functional blockade. Basic dialkylamine-terminated analogs were found to weakly bind the hERG channel and provided marked improvement in a functional patch-clamp assay versus previously reported antagonists of the series.
Judd
Andrew S
AS
Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. andrew.judd@abbott.com
Souers
Andrew J
AJ
Wodka
Dariusz
D
Zhao
Gang
G
Mulhern
Mathew M
MM
Iyengar
Rajesh R
RR
Gao
Ju
J
Lynch
John K
JK
Freeman
Jennifer C
JC
Falls
H Douglas
HD
Brodjian
Sevan
S
Dayton
Brian D
BD
Reilly
Regina M
RM
Gintant
Gary
G
Limberis
James T
JT
Mikhail
Ann
A
Leitza
Sandra T
ST
Houseman
Kathryn A
KA
Diaz
Gilbert
G
Bush
Eugene N
EN
Shapiro
Robin
R
Knourek-Segel
Victoria
V
Hernandez
Lisa E
LE
Marsh
Kennan C
KC
Sham
Hing L
HL
Collins
Christine A
CA
Kym
Philip R
PR
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D018408:Patch-Clamp Techniques; D010599:Pharmacokinetics; D011979:Receptors, Pituitary Hormone / Q000037:antagonists & inhibitors*
D000577:Amides; D002867:Chromones; D051638:Ether-A-Go-Go Potassium Channels; D011979:Receptors, Pituitary Hormone; C092274:melanin-concentrating hormone receptor