The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release. The synthesis and biological evaluation of these compounds are reported.
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Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3.
Bioorg Med Chem Lett
October 2004
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park IL 60064, USA.
Prior SAR studies on 2-amino-8-alkoxyquinoline MCHr1 antagonists demonstrated that compounds with acyclic amide-containing sidechains displayed exceptional binding and functional potency, but negligible CNS penetration. Related analogs with acyclic benzylamine-containing sidechains showed greatly improved CNS exposure, but suffered in functional potency. In this report, we demonstrate that cyclization of these benzylic amine sidechains affords compounds that combine the best elements of potency and CNS penetration among this class of antagonists.
View Article and Find Full Text PDFSynthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2.
Bioorg Med Chem Lett
October 2004
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
The continued SAR investigation of 2-amino-8-alkoxy quinolines as melanin concentrating hormone receptor-1 (MCHr1) antagonists is reported. Prior hit-to-lead efforts resulted in the identification of 1 as a robust MCHr1 antagonist. Further delineation of the structural parameters essential for MCHr1-binding affinity of this class of nontraditional GPCR ligands resulted in the identification of compounds such as 33, 34 and 37, which demonstrate single digit nanomolar antagonism of MCHr1-mediated Ca(2+) release.
View Article and Find Full Text PDFSynthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 1.
Bioorg Med Chem Lett
October 2004
Metabolic Diseases Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
A high-throughput screen was performed in order to identify chemotypes that are bound by the melanin concentrating hormone receptor-1 (MCHr1). A novel 2-amino-8-alkoxyquinoline compound (1) was identified and subsequently optimized using a parallel and automated procedure for the rapid production of multiple analogs. The structure-activity relationships that emerged from this effort are described, along with selected pharmacokinetic parameters of compound (d)-61 when dosed orally in diet-induced obese mice.
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