Conformationally biased P3 amide replacements of beta-secretase inhibitors

Shawn J Stachel; Craig A Coburn; Thomas G Steele; Min-Chi Crouthamel; Beth L Pietrak; Ming-Tain Lai; M Katharine Holloway; Sanjeev K Munshi; Samuel L Graham; Joseph P Vacca

doi:10.1016/j.bmcl.2005.10.032

Conformationally biased P3 amide replacements of beta-secretase inhibitors

Bioorg Med Chem Lett. 2006 Feb;16(3):641-4. doi: 10.1016/j.bmcl.2005.10.032. Epub 2005 Nov 2.

Authors

Shawn J Stachel¹, Craig A Coburn, Thomas G Steele, Min-Chi Crouthamel, Beth L Pietrak, Ming-Tain Lai, M Katharine Holloway, Sanjeev K Munshi, Samuel L Graham, Joseph P Vacca

Affiliation

¹ Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. shawn_stachel@merck.com

PMID: 16263281
DOI: 10.1016/j.bmcl.2005.10.032

Abstract

We have synthesized and evaluated a series of conformationally biased P3 amide replacements based on an isophthalamide lead structure. The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described.

MeSH terms

Amides / chemistry*
Amides / pharmacology
Amyloid Precursor Protein Secretases
Drug Design
Endopeptidases / metabolism*
Inhibitory Concentration 50
Models, Molecular
Phthalic Acids / chemistry
Protease Inhibitors / chemical synthesis*
Protease Inhibitors / pharmacology
Structure-Activity Relationship

Substances

Amides
Phthalic Acids
Protease Inhibitors
isophthalate
Amyloid Precursor Protein Secretases
Endopeptidases