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Publication Abstract from PubMed

Verubecestat 3 (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor currently undergoing Phase 3 clinical evaluation for the treatment of mild to moderate and prodromal Alzheimer's disease. Although not selective over the closely related aspartyl protease BACE2, verubecestat has high selectivity for BACE1 over other key aspartyl proteases, notably cathepsin D, and profoundly lowers CSF and brain Abeta levels in rats and nonhuman primates and CSF Abeta levels in humans. In this annotation, we describe the discovery of 3, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization.

Discovery of the 3-Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)-A beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer's Disease.,Scott JD, Li SW, Brunskill AP, Chen X, Cox K, Cumming JN, Forman M, Gilbert EJ, Hodgson RA, Hyde LA, Jiang Q, Iserloh U, Kazakevich I, Kuvelkar R, Mei H, Meredith J, Misiaszek J, Orth P, Rossiter LM, Slater M, Stone J, Strickland CO, Voigt JH, Wang G, Wang H, Wu Y, Greenlee WJ, Parker EM, Kennedy ME, Stamford AW J Med Chem. 2016 Dec 8;59(23):10435-10450. Epub 2016 Nov 18. PMID:27933948^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.