title: The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity.
abstract: A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.
authors.affiliation: Respiratory and Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. john.cumming@astrazeneca.com
authors.forename: John G
authors.initials: JG
authors.lastname: Cumming
authors.forename: Justin F
authors.initials: JF
authors.lastname: Bower
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Alan
authors.initials: A
authors.lastname: Faull
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Poyser
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.forename: Benjamin
authors.initials: B
authors.lastname: McDermott
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.forename: Julian
authors.initials: J
authors.lastname: Hudson
authors.forename: Michael
authors.initials: M
authors.lastname: James
authors.forename: Jon
authors.initials: J
authors.lastname: Winter
authors.forename: Christine
authors.initials: C
authors.lastname: Wood
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D004285:Dogs; D015195:Drug Design; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007249:Inflammation / Q000188:drug therapy; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C515334:CCR2 protein, human; D051638:Ether-A-Go-Go Potassium Channels; C575094:N-(3,4-dichlorophenyl)-4-((2R)-4-isopropylpiperazine-2-carbonyl)piperazine-1-carboxamide; D010879:Piperazines; D054390:Receptors, CCR2; D002118:Calcium