Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators

Scott D Kuduk; Christina N Di Marco; Jonathan R Saffold; William J Ray; Lei Ma; Marion Wittmann; Kenneth A Koeplinger; Charles D Thompson; George D Hartman; Mark T Bilodeau; Douglas C Beshore

doi:10.1016/j.bmcl.2014.01.012

Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1417-20. doi: 10.1016/j.bmcl.2014.01.012. Epub 2014 Jan 13.

Affiliations

¹ Department of Medicinal Chemistry, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA. Electronic address: [email protected].
² Department of Medicinal Chemistry, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA.
³ Department of Alzheimer's Research, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA.
⁴ Department of Drug Metabolism, Merck Research Laboratories, Sumneytown Pike, PO Box 4, West Point, PA 19486, USA.

PMID: 24485781
DOI: 10.1016/j.bmcl.2014.01.012

Abstract

A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series.

Keywords: Allosteric modulator; Alzheimer’s disease; M(1); Muscarinic; P-glycoprotein.

MeSH terms

Allosteric Regulation
Amides / chemical synthesis
Amides / chemistry*
Amides / metabolism
Animals
CHO Cells
Cricetinae
Cricetulus
Mice
Naphthalenes / chemistry*
Protein Binding
Quinolizidines / chemistry*
Receptor, Muscarinic M1 / chemistry
Receptor, Muscarinic M1 / metabolism*
Structure-Activity Relationship

Substances

Amides
Naphthalenes
Quinolizidines
Receptor, Muscarinic M1
naphthalene