title: Optimization of chromone-2-carboxamide melanin concentrating hormone receptor 1 antagonists: assessment of potency, efficacy, and cardiovascular safety.
abstract: 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.
authors.affiliation: 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
authors.forename: John K
authors.initials: JK
authors.lastname: Lynch
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Freeman
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Judd
authors.forename: Rajesh
authors.initials: R
authors.lastname: Iyengar
authors.forename: Mathew
authors.initials: M
authors.lastname: Mulhern
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.forename: James J
authors.initials: JJ
authors.lastname: Napier
authors.forename: Dariusz
authors.initials: D
authors.lastname: Wodka
authors.forename: Sevan
authors.initials: S
authors.lastname: Brodjian
authors.forename: Brian D
authors.initials: BD
authors.lastname: Dayton
authors.forename: Doug
authors.initials: D
authors.lastname: Falls
authors.forename: Christopher
authors.initials: C
authors.lastname: Ogiela
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Campbell
authors.forename: James S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: Lisa
authors.initials: L
authors.lastname: Hernandez
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Robin
authors.initials: R
authors.lastname: Shapiro
authors.forename: Victoria
authors.initials: V
authors.lastname: Knourek-Segel
authors.forename: Brian
authors.initials: B
authors.lastname: Droz
authors.forename: Eugene
authors.initials: E
authors.lastname: Bush
authors.forename: Michael
authors.initials: M
authors.lastname: Brune
authors.forename: Lee C
authors.initials: LC
authors.lastname: Preusser
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Fryer
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Reinhart
authors.forename: Kathryn
authors.initials: K
authors.lastname: Houseman
authors.forename: Gilbert
authors.initials: G
authors.lastname: Diaz
authors.forename: Ann
authors.initials: A
authors.lastname: Mikhail
authors.forename: James T
authors.initials: JT
authors.lastname: Limberis
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Christine A
authors.initials: CA
authors.lastname: Collins
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
mesh_terms: 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
chemical_list: 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