23 research outputs found
Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons
Stereoselective Synthesis of Novel Dipeptide β-Turn Mimetics Targeting Melanocortin Peptide Receptors
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
Design and Synthesis of γ- and δ‑Lactam M<sub>1</sub> Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M<sub>1</sub>‑Selective PAM with Weak Agonist Activity
Recent
data demonstrated that activation of the muscarinic M<sub>1</sub> receptor
by a subtype-selective positive allosteric modulator
(PAM) contributes to the gastrointestinal (GI) and cardiovascular
(CV) cholinergic adverse events (AEs) previously attributed to M<sub>2</sub> and M<sub>3</sub> activation. These studies were conducted
using PAMs that also exhibited allosteric agonist activity, leaving
open the possibility that direct activation by allosteric agonism,
rather than allosteric modulation, could be responsible for the adverse
effects. This article describes the design and synthesis of lactam-derived
M<sub>1</sub> PAMs that address this hypothesis. The lead molecule
from this series, compound <b>1</b> (PF-06827443), is a potent,
low-clearance, orally bioavailable, and CNS-penetrant M<sub>1</sub>-selective PAM with minimal agonist activity. Compound <b>1</b> was tested in dose escalation studies in rats and dogs and was found
to induce cholinergic AEs and convulsion at therapeutic indices similar
to previous compounds with more agonist activity. These findings provide
preliminary evidence that positive allosteric modulation of M<sub>1</sub> is sufficient to elicit cholinergic AEs
Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment
Design and Synthesis of γ- and δ‑Lactam M<sub>1</sub> Positive Allosteric Modulators (PAMs): Convulsion and Cholinergic Toxicity of an M<sub>1</sub>‑Selective PAM with Weak Agonist Activity
Recent
data demonstrated that activation of the muscarinic M<sub>1</sub> receptor
by a subtype-selective positive allosteric modulator
(PAM) contributes to the gastrointestinal (GI) and cardiovascular
(CV) cholinergic adverse events (AEs) previously attributed to M<sub>2</sub> and M<sub>3</sub> activation. These studies were conducted
using PAMs that also exhibited allosteric agonist activity, leaving
open the possibility that direct activation by allosteric agonism,
rather than allosteric modulation, could be responsible for the adverse
effects. This article describes the design and synthesis of lactam-derived
M<sub>1</sub> PAMs that address this hypothesis. The lead molecule
from this series, compound <b>1</b> (PF-06827443), is a potent,
low-clearance, orally bioavailable, and CNS-penetrant M<sub>1</sub>-selective PAM with minimal agonist activity. Compound <b>1</b> was tested in dose escalation studies in rats and dogs and was found
to induce cholinergic AEs and convulsion at therapeutic indices similar
to previous compounds with more agonist activity. These findings provide
preliminary evidence that positive allosteric modulation of M<sub>1</sub> is sufficient to elicit cholinergic AEs