8 research outputs found
Stereoselective Synthesis of a Dipyridyl Transient Receptor Potential Vanilloid‑3 (TRPV3) Antagonist
An
efficient asymmetric synthesis of dipyridyl TRPV3 antagonist <b>1</b> is reported. The four-step route involves two C–C
bond-forming steps, a highly diastereoselective alkene hydration,
and asymmetric ketone hydrosilylation in 97% ee
Structure-acitivity studies and analgesic efficacy of N-(3-pyridinyl)-bridged bicyclic diamines, exceptionally potent agonists at nicotinic acetylcholine receptors
A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha4beta2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds
Substituted Indazoles as Na<sub>v</sub>1.7 Blockers for the Treatment of Pain
The
genetic validation for the role of the Na<sub>v</sub>1.7 voltage-gated
ion channel in pain signaling pathways makes it an appealing target
for the potential development of new pain drugs. The utility of nonselective
Na<sub>v</sub> blockers is often limited due to adverse cardiovascular
and CNS side effects. We sought more selective Na<sub>v</sub>1.7 blockers
with oral activity, improved selectivity, and good druglike properties.
The work described herein focused on a series of 3- and 4-substituted
indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but
poor rat pharmacokinetics. Optimization of 4-substituted indazoles
yielded two compounds, <b>27</b> and <b>48</b>, that exhibited
good in vitro and in vivo activity with improved rat pharmacokinetic
profiles. Both <b>27</b> and <b>48</b> demonstrated robust
activity in the acute rat monoiodoacetate-induced osteoarthritis model
of pain, and subchronic dosing of <b>48</b> showed a shift to
a lower EC<sub>50</sub> over 7 days
Substituted Indazoles as Na<sub>v</sub>1.7 Blockers for the Treatment of Pain
The
genetic validation for the role of the Na<sub>v</sub>1.7 voltage-gated
ion channel in pain signaling pathways makes it an appealing target
for the potential development of new pain drugs. The utility of nonselective
Na<sub>v</sub> blockers is often limited due to adverse cardiovascular
and CNS side effects. We sought more selective Na<sub>v</sub>1.7 blockers
with oral activity, improved selectivity, and good druglike properties.
The work described herein focused on a series of 3- and 4-substituted
indazoles. SAR studies of 3-substituted indazoles yielded analog <b>7</b> which demonstrated good in vitro and in vivo activity but
poor rat pharmacokinetics. Optimization of 4-substituted indazoles
yielded two compounds, <b>27</b> and <b>48</b>, that exhibited
good in vitro and in vivo activity with improved rat pharmacokinetic
profiles. Both <b>27</b> and <b>48</b> demonstrated robust
activity in the acute rat monoiodoacetate-induced osteoarthritis model
of pain, and subchronic dosing of <b>48</b> showed a shift to
a lower EC<sub>50</sub> over 7 days
Synthesis and Pharmacology of (Pyridin-2-yl)methanol Derivatives as Novel and Selective Transient Receptor Potential Vanilloid 3 Antagonists
Transient receptor
potential vanilloid 3 (TRPV3) is a Ca<sup>2+</sup>- and Na<sup>+</sup>-permeable channel with a unique expression pattern.
TRPV3 is found in both neuronal and non-neuronal tissues, including
dorsal root ganglia, spinal cord, and keratinocytes. Recent studies
suggest that TRPV3 may play a role in inflammation, pain sensation,
and skin disorders. TRPV3 studies have been challenging, in part due
to a lack of research tools such as selective antagonists. Herein,
we provide the first detailed report on the development of potent
and selective TRPV3 antagonists featuring a pyridinyl methanol moiety.
Systematic optimization of pharmacological, physicochemical, and ADME
properties of original lead <b>5a</b> resulted in identification
of a novel and selective TRPV3 antagonist <b>74a</b>, which
demonstrated a favorable preclinical profile in two different models
of neuropathic pain as well as in a reserpine model of central pain