5 research outputs found
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
The Discovery of <i>N</i>‑((2<i>H</i>‑Tetrazol-5-yl)methyl)-4-((<i>R</i>)‑1-((5<i>r</i>,8<i>R</i>)‑8‑(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiro[4.5]dec-3-en-1-yl)-4,4-dimethylpentyl)benzamide (SCH 900822): A Potent and Selective Glucagon Receptor Antagonist
A novel
series of spiroimidazolone-based antagonists of the human
glucagon receptor (hGCGR) has been developed. Our efforts have led
to compound <b>1</b>, <i>N</i>-((2<i>H</i>-tetrazol-5-yl)Âmethyl)-4-((<i>R</i>)-1-((5<i>r</i>,8<i>R</i>)-8-(<i>tert</i>-butyl)-3-(3,5-dichlorophenyl)-2-oxo-1,4-diazaspiroÂ[4.5]Âdec-3-en-1-yl)-4,4-dimethylpentyl)Âbenzamide
(SCH 900822), a potent hGCGR antagonist with exceptional selectivity
over the human glucagon-like peptide-1 receptor. Oral administration
of <b>1</b> lowered 24 h nonfasting glucose levels in imprinting
control region mice on a high fat diet with diet-induced obesity following
single oral doses of 3 and 10 mg/kg. Furthermore, compound <b>1</b>, when dosed orally, was found to decrease fasting blood glucose
at 30 mg/kg in a streptozotocin-treated, diet-induced obesity mouse
pharmacodynamic assay and blunt exogenous glucagon-stimulated glucose
excursion in prediabetic mice
Structure-Based Design of an Iminoheterocyclic β‑Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Aβ in Nonhuman Primates
We
describe successful efforts to optimize the in vivo profile and address
off-target liabilities of a series of BACE1 inhibitors represented
by <b>6</b> that embodies the recently validated fused pyrrolidine
iminopyrimidinone scaffold. Employing structure-based design, truncation
of the cyanophenyl group of <b>6</b> that binds in the S3 pocket
of BACE1 followed by modification of the thienyl group in S1 was pursued.
Optimization of the pyrimidine substituent that binds in the S2′–S2″
pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier
analogues in this series and imparted high BACE1 affinity. These efforts
resulted in the discovery of difluorophenyl analogue <b>9</b> (MBi-4), which robustly lowered CSF and cortex Aβ<sub>40</sub> in both rats and cynomolgus monkeys following a single oral dose.
Compound <b>9</b> represents a unique molecular shape among
BACE inhibitors reported to potently lower central Aβ in nonrodent
preclinical species
MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology
The
emergence and evolution of new immunological cancer therapies has
sparked a rapidly growing interest in discovering novel pathways to
treat cancer. Toward this aim, a novel series of pyrrolidine derivatives
(compound <b>5</b>) were identified as potent inhibitors of
ERK1/2 with excellent kinase selectivity and dual mechanism of action
but suffered from poor pharmacokinetics (PK). The challenge of PK
was overcome by the discovery of a novel 3Â(<i>S</i>)-thiomethyl
pyrrolidine analog <b>7</b>. Lead optimization through focused
structure–activity relationship led to the discovery of a clinical
candidate <b>MK-8353</b> suitable for twice daily oral dosing
as a potential new cancer therapeutic