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Bioorg Med Chem Lett. 2009 Sep 1;19(17):4993-5. doi: 10.1016/j.bmcl.2009.07.071. Epub 2009 Jul 17.

A conformational constraint improves a beta-secretase inhibitor but for an unexpected reason.

Author information

  • 1Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., West Point, PA 19486, USA. ivory_hills@merck.com


During our ongoing efforts to develop a small molecule inhibitor targeting the beta-amyloid cleaving enzyme (BACE-1), we discovered a class of compounds bearing an aminoimidazole motif. Initial optimization led to potent compounds that have high Pgp efflux ratios. Crystal structure-aided design furnished conformationally constrained compounds that are both potent and have relatively low Pgp efflux ratios. Computational studies performed after these optimizations suggest that the introduction of the constraint enhances potency via additional hydrophobic interactions rather than conformational restriction.

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