Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety.
Evaluation of multiple structurally distinct series of melanin concentrating hormone receptor 1 antagonists in an anesthetized rat cardiovascualar assay led to the identification of a chromone-2-carboxamide series as having excellent safety against the chosen cardiovascular endpoints at high drug concentrations in the plasma and brain. Optimization of this series led to considerable improvements in affinity, functional potency, and pharmacokinetic profile. This led to the identification of a 7-fluorochromone-2-carboxamide (22) that was orally efficacious in a diet-induced obese mouse model, retained a favorable cardiovascular profile in rat, and demonstrated dramatic improvement in effects on mean arterial pressure in our dog cardiovascular model compared to other series reported by our group. However, this analogue also led to prolongation of the QT interval in the dog that was linked to affinity for hERG channel and unexpectedly potent functional blockade of this ion channel.
Lynch
John K
JK
Metabolic Disease Research, Integrative Pharmacology, Process Chemistry, and Exploratory Pharmacokinetics, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. john.k.lynch@abbott.com
Freeman
Jennifer C
JC
Judd
Andrew S
AS
Iyengar
Rajesh
R
Mulhern
Mathew
M
Zhao
Gang
G
Napier
James J
JJ
Wodka
Dariusz
D
Brodjian
Sevan
S
Dayton
Brian D
BD
Falls
Doug
D
Ogiela
Christopher
C
Reilly
Regina M
RM
Campbell
Thomas J
TJ
Polakowski
James S
JS
Hernandez
Lisa
L
Marsh
Kennan C
KC
Shapiro
Robin
R
Knourek-Segel
Victoria
V
Droz
Brian
B
Bush
Eugene
E
Brune
Michael
M
Preusser
Lee C
LC
Fryer
Ryan M
RM
Reinhart
Glenn A
GA
Houseman
Kathryn
K
Diaz
Gilbert
G
Mikhail
Ann
A
Limberis
James T
JT
Sham
Hing L
HL
Collins
Christine A
CA
Kym
Philip R
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D000215:Acylation; D000818:Animals; D019540:Area Under Curve; D052117:Benzodioxoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000139:chemically induced*; D002460:Cell Line; D002867:Chromones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006339:Heart Rate / Q000187:drug effects; D007202:Indicators and Reagents; D051379:Mice; D008810:Mice, Inbred C57BL; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D052117:Benzodioxoles; D002867:Chromones; D007202:Indicators and Reagents; C491208:MCHR1 protein, rat; C515236:N-(1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl)-7-fluoro-4-oxo-4H-chromene-2-carboxamide; D015221:Potassium Channels; D017481:Receptors, Somatostatin; D002118:Calcium