26 research outputs found
Lead optimization of a pyrazole sulfonamide series of trypanosoma brucei N -myristoyltransferase inhibitors:Identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human african trypanosomiasis
[Image: see text] Trypanosoma bruceiN-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood–brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT
A New Method for the Formation of Octahydroindole Alkaloids via the Intramolecular Diels−Alder Reaction of 2-Amidofurans
Cycloaddition−Rearrangement Sequence of 2-Amido Substituted Furans as a Method of Synthesizing Hexahydroindolinones
A Cycloaddition Approach toward the Synthesis of Substituted Indolines and Tetrahydroquinolines
Strategies toward optimization of the metabolism of a series of serotonin-4 partial agonists: investigation of azetidines as piperidine isosteres
Two Routes to 4‑Fluorobenzisoxazol-3-one in the Synthesis of a 5‑HT<sub>4</sub> Partial Agonist
A potent 5-HT<sub>4</sub> partial agonist, <b>1</b> (PF-04995274),
targeted for the treatment of Alzheimer’s disease and cognitive
impairment, has been prepared on a multi-kilogram scale. The initial
synthetic route, that proceeded through a 4-substituted 3-hydroxybenzisoxazole
core, gave an undesired benzoxazolinone through a Lossen-type rearrangement.
Route scouting led to two new robust routes to the desired 4-substituted
core. Process development led to the efficient assembly of the API
on a pilot plant scale under process-friendly conditions with enhanced
throughput. In addition, crystallization of a hemicitrate salt of
the API with pharmaceutically beneficial properties was developed
to enable progression of clinical studies
Harnessing biosynthesis and quantitative NMR for late stage functionalization of lead molecules: Application to the M1 positive allosteric modulator (PAM) program
Cerebrospinal Fluid Amyloid-β (Aβ) as an Effect Biomarker for Brain Aβ Lowering Verified by Quantitative Preclinical Analyses
Discovery of Trifluoromethyl Glycol Carbamates as Potent and Selective Covalent Monoacylglycerol Lipase (MAGL) Inhibitors for Treatment of Neuroinflammation
Monoacylglycerol lipase (MAGL) inhibition
provides a potential
treatment approach to neuroinflammation through modulation of both
the endocannabinoid pathway and arachidonoyl signaling in the central
nervous system (CNS). Herein we report the discovery of compound <b>15</b> (PF-06795071), a potent and selective covalent MAGL inhibitor,
featuring a novel trifluoromethyl glycol leaving group that confers
significant physicochemical property improvements as compared with
earlier inhibitor series with more lipophilic leaving groups. The
design strategy focused on identifying an optimized leaving group
that delivers MAGL potency, serine hydrolase selectivity, and CNS
exposure while simultaneously reducing log <i>D</i>, improving solubility, and minimizing chemical lability. Compound <b>15</b> achieves excellent CNS exposure, extended 2-AG elevation
effect in vivo, and decreased brain inflammatory
markers in response to an inflammatory challenge