4 research outputs found
Discovery of soticlestat, a potent and selective inhibitor for cholesterol 24-hydroxylase (CH24H)
Cholesterol 24-hydroxylase
(CH24H, CYP46A1), a brain-specific cytochrome
P450 (CYP) family enzyme, plays a role in the homeostasis of brain
cholesterol by converting cholesterol to 24S-hydroxycholesterol
(24HC). Despite a wide range of potential of CH24H as a drug target,
no potent and selective inhibitors have been identified. Here, we
report on the structure-based drug design (SBDD) of novel 4-arylpyridine
derivatives based on the X-ray co-crystal structure of hit derivative 1b. Optimization of 4-arylpyridine derivatives led us to identify 3v ((4-benzyl-4-hydroxypiperidin-1-yl)(2,4′-bipyridin-3-yl)methanone,
IC50 = 7.4 nM) as a highly potent, selective, and brain-penetrant
CH24H inhibitor. Following oral administration to mice, 3v resulted in a dose-dependent reduction of 24HC levels in the brain
(1, 3, and 10 mg/kg). Compound 3v (soticlestat, also
known as TAK-935) is currently under clinical investigation for the
treatment of Dravet syndrome and Lennox-Gastaut syndrome as a novel
drug class for epilepsies
Soticlestat, a novel cholesterol 24-hydroxylase inhibitor shows a therapeutic potential for neural hyperexcitation in mice
Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor
The
aspartic proteinase renin is an attractive target for the treatment
of hypertension and cardiovascular/renal disease such as chronic kidney
disease and heart failure. We introduced an S1′ site binder
into the lead compound <b>1</b> guided by structure-based drug
design (SBDD), and further optimization of physicochemical properties
led to the discovery of benzimidazole derivative <b>10</b> (1-(4-methoxybutyl)-<i>N</i>-(2-methylpropyl)-<i>N</i>-[(3<i>S</i>,5<i>R</i>)-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1<i>H-</i>benzimidazole-2-carboxamide hydrochloride, TAK-272) as
a highly potent and orally active renin inhibitor. Compound <b>10</b> demonstrated good oral bioavailability (BA) and long-lasting
efficacy in rats. Compound <b>10</b> is currently in clinical
trials