Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 3

Bioorganic & Medicinal Chemistry Letters
Andrew J SouersPhilip R Kym

Abstract

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. This is exemplified by compound 21, which has sub-nanomolar MCHr1 binding affinity, good functional potency, and excellent CNS exposure over 24h.

References

Oct 2, 2002·International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity·O Della-ZuanaN Levens
Sep 3, 2004·Bioorganic & Medicinal Chemistry Letters·Andrew J SouersPhilip R Kym
Sep 3, 2004·Bioorganic & Medicinal Chemistry Letters·Anil VasudevanPhilip R Kym

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Citations

Jun 14, 2005·Bioorganic & Medicinal Chemistry Letters·Anil VasudevanPhilip R Kym
Jun 15, 2005·Bioorganic & Medicinal Chemistry Letters·Tao GuoDoug W Hobbs
Nov 14, 2007·The Journal of Organic Chemistry·Denise AndersenMike Martinelli

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