An evaluation of 3,4-methylenedioxy phenyl replacements in the aminopiperidine chromone class of MCHr1 antagonists.
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles.
Iyengar
Rajesh R
RR
Metabolic Disease Research, Metabolic Disease Research, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. rajesh.iyengar@abbott.com
Lynch
John K
JK
Mulhern
Mathew M
MM
Judd
Andrew S
AS
Freeman
Jennifer C
JC
Gao
Ju
J
Souers
Andrew J
AJ
Zhao
Gang
G
Wodka
Dariusz
D
Doug Falls
H
H
Brodjian
Sevan
S
Dayton
Brian D
BD
Reilly
Regina M
RM
Swanson
Sue
S
Su
Zhi
Z
Martin
Ruth L
RL
Leitza
Sandra T
ST
Houseman
Kathryn A
KA
Diaz
Gilbert
G
Collins
Christine A
CA
Sham
Hing L
HL
Kym
Philip R
PR
D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002867:Chromones; D003429:Cross Reactions; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002867:Chromones; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D006571:Heterocyclic Compounds; C000606913:KCNH2 protein, human; C103263:MCHR1 protein, human; D010880:Piperidines; D017481:Receptors, Somatostatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human