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

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

Author information

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.

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

PMID:
26195137
DOI:
10.1016/j.bmcl.2015.06.082
[Indexed for MEDLINE]

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