Discovery of a Tetrahydrobenzisoxazole Series of γ‑Secretase Modulators

The design and synthesis of a new series of tetrahydrobenzisoxazoles as modulators of γ-secretase activity and their structure–activity relationship (SAR) will be detailed. Several compounds are active γ-secretase modulators (GSMs) with good to excellent selectivity for the reduction of Aβ₄₂ in the cellular assay. Compound <b>14a</b> was tested <i>in vivo</i> in a nontransgenic rat model and was found to significantly reduce Aβ₄₂ in the CNS compartment compared to vehicle-treated animals (up to 58% reduction of cerebrospinal fluid Aβ₄₂ as measured 3 h after an acute oral dosing at 30 mg/kg)

Himbacine-Derived Thrombin Receptor Antagonists: C₇‑Spirocyclic Analogues of Vorapaxar

We have synthesized several C₇-spirocyclic analogues of vorapaxar and evaluated their in vitro activities against PAR-1 receptor. Some of these analogues showed activities and rat plasma levels comparable to vorapaxar. Compound <b>5c</b> from this series showed excellent PAR-1 activity (<i>K</i>_i = 5.1 nM). We also present a model of these spirocyclic compounds docked to the PAR-1 receptor based on the X-ray crystal structure of vorapaxar bound to PAR-1 receptor. This model explains some of the structure–activity relationships in this series

Discovery of MK-8282 as a Potent G‑Protein-Coupled Receptor 119 Agonist for the Treatment of Type 2 Diabetes

The ever-growing prevalence of type 2 diabetes in the world has necessitated an urgent need for multiple orally effective agents that can regulate glucose homeostasis with a concurrent reduction in body weight. G-Protein coupled receptor 119 (GPR119) is a GPCR target at which agonists have demonstrated glucose-dependent insulin secretion and shows beneficial effects on glycemic control. Herein, we describe our efforts leading to the identification of a potent, oral GPR-119 agonist, MK-8282, which shows improved glucose tolerance in multiple animal models and has excellent off-target profile. The key design elements in the compounds involved a combination of a fluoro-pyrimidine and a conformationally constrained bridged piperidine to impart good potency and efficacy

Discovery of the 3‑Imino-1,2,4-thiadiazinane 1,1-Dioxide Derivative Verubecestat (MK-8931)–A β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Verubecestat <b>3</b> (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-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 Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of <b>3</b>, 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 β‑Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor for the Treatment of Alzheimer’s Disease

Verubecestat <b>3</b> (MK-8931), a diaryl amide-substituted 3-imino-1,2,4-thiadiazinane 1,1-dioxide derivative, is a high-affinity β-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 Aβ levels in rats and nonhuman primates and CSF Aβ levels in humans. In this annotation, we describe the discovery of <b>3</b>, including design, validation, and selected SAR around the novel iminothiadiazinane dioxide core as well as aspects of its preclinical and Phase 1 clinical characterization