Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency

Melissa Egbertson; Georgia B McGaughey; Steven M Pitzenberger; Shaun R Stauffer; Craig A Coburn; Shawn J Stachel; Wenjin Yang; James C Barrow; Lou Anne Neilson; Melody McWherter; Debra Perlow; Bruce Fahr; Sanjeev Munshi; Timothy J Allison; Katharine Holloway; Harold G Selnick; ZhiQiang Yang; John Swestock; Adam J Simon; Sethu Sankaranarayanan; Dennis Colussi; Katherine Tugusheva; Ming-Tain Lai; Beth Pietrak; Shari Haugabook; Lixia Jin; I-W Chen; Marie Holahan; Maria Stranieri-Michener; Jacquelynn J Cook; Joseph Vacca; Samuel L Graham

doi:10.1016/j.bmcl.2015.06.082

Methyl-substitution of an iminohydantoin spiropiperidine β-secretase (BACE-1) inhibitor has a profound effect on its potency

Bioorg Med Chem Lett. 2015 Nov 1;25(21):4812-4819. doi: 10.1016/j.bmcl.2015.06.082. Epub 2015 Jun 29.

Authors

Melissa Egbertson¹, Georgia B McGaughey², Steven M Pitzenberger³, Shaun R Stauffer⁴, Craig A Coburn⁴, Shawn J Stachel⁴, Wenjin Yang⁵, James C Barrow⁴, Lou Anne Neilson⁴, Melody McWherter⁴, Debra Perlow⁴, Bruce Fahr⁵, Sanjeev Munshi⁶, Timothy J Allison⁷, Katharine Holloway², Harold G Selnick⁸, ZhiQiang Yang⁴, John Swestock⁹, Adam J Simon¹⁰, Sethu Sankaranarayanan¹⁰, Dennis Colussi¹⁰, Katherine Tugusheva¹⁰, Ming-Tain Lai¹⁰, Beth Pietrak¹⁰, Shari Haugabook¹⁰, Lixia Jin¹¹, I-W Chen¹¹, Marie Holahan¹², Maria Stranieri-Michener¹², Jacquelynn J Cook¹², Joseph Vacca⁴, Samuel L Graham⁴

Affiliations

¹ Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: melissaegbertson@gmail.com.
² Structural Chemistry, WP53-3 Merck and Co., West Point, PA 19486, USA.
³ NMR Structure Elucidation, Process and Analytical Chemistry, WP14-1 Merck and Co., West Point, PA 19486, USA.
⁴ Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA.
⁵ Sunesis Pharmaceuticals, 395 Oyster Point Blvd. Ste. 400, South San Francisco, CA 94080, USA.
⁶ Structural Biology, WP 14-2 Merck and Co., West Point, PA 19486, USA.
⁷ Structural Biology, WP 14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: timothy.j.allison@gmail.com.
⁸ Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: selnickh@gmail.com.
⁹ Process Chemistry, WP 14-1 Merck and Co., West Point, PA 19486, USA.
¹⁰ Pharmacology, WP 26-1 Merck and Co., West Point, PA 19486, USA.
¹¹ Drug Metabolism, WP 75-B Merck and Co., West Point, PA 19486, USA.
¹² Imaging Research, WP 44c Merck and Co., West Point, PA 19486, USA.

PMID: 26195137
DOI: 10.1016/j.bmcl.2015.06.082

Abstract

The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

Keywords: Amyloid; Beta secretase; Magic methyl effect; Spiropiperidine.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / metabolism
Crystallography, X-Ray
Dose-Response Relationship, Drug
Humans
Hydantoins / chemical synthesis
Hydantoins / chemistry*
Hydantoins / pharmacology*
Methylation
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Hydantoins
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human