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The design and synthesis of novel, potent and orally bioavailable N-aryl piperazine-1-carboxamide CCR2 antagonists with very high hERG selectivity.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2012 Jun 15; Vol. 22 (12), pp. 3895-9. Date of Electronic Publication: 2012 May 02. - Publication Year :
- 2012
-
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.<br /> (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Anti-Inflammatory Agents pharmacokinetics
Anti-Inflammatory Agents pharmacology
Calcium metabolism
Dogs
Drug Design
Ether-A-Go-Go Potassium Channels antagonists & inhibitors
Ether-A-Go-Go Potassium Channels metabolism
Humans
Hydrophobic and Hydrophilic Interactions
Inflammation drug therapy
Piperazines pharmacokinetics
Piperazines pharmacology
Protein Binding
Rats
Receptors, CCR2 metabolism
Anti-Inflammatory Agents chemical synthesis
Piperazines chemical synthesis
Receptors, CCR2 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 22
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 22608963
- Full Text :
- https://doi.org/10.1016/j.bmcl.2012.04.118