5 research outputs found
Molecular Pharmacology of Selective Na<sub>V</sub>1.6 and Dual Na<sub>V</sub>1.6/Na<sub>V</sub>1.2 Channel Inhibitors that Suppress Excitatory Neuronal Activity Ex Vivo
Voltage-gated sodium channel (NaV) inhibitors
are used
to treat neurological disorders of hyperexcitability such as epilepsy.
These drugs act by attenuating neuronal action potential firing to
reduce excitability in the brain. However, all currently available
NaV-targeting antiseizure medications nonselectively inhibit
the brain channels NaV1.1, NaV1.2, and NaV1.6, which potentially limits the efficacy and therapeutic
safety margins of these drugs. Here, we report on XPC-7724 and XPC-5462,
which represent a new class of small molecule NaV-targeting
compounds. These compounds specifically target inhibition of the NaV1.6 and NaV1.2 channels, which are abundantly expressed
in excitatory pyramidal neurons. They have a > 100-fold molecular
selectivity against NaV1.1 channels, which are predominantly
expressed in inhibitory neurons. Sparing NaV1.1 preserves
the inhibitory activity in the brain. These compounds bind to and
stabilize the inactivated state of the channels thereby reducing the
activity of excitatory neurons. They have higher potency, with longer
residency times and slower off-rates, than the clinically used antiseizure
medications carbamazepine and phenytoin. The neuronal selectivity
of these compounds is demonstrated in brain slices by inhibition of
firing in cortical excitatory pyramidal neurons, without impacting
fast spiking inhibitory interneurons. XPC-5462 also suppresses epileptiform
activity in an ex vivo brain slice seizure model, whereas XPC-7224
does not, suggesting a possible requirement of Nav1.2 inhibition in
0-Mg2+- or 4-AP-induced brain slice seizure models. The
profiles of these compounds will facilitate pharmacological dissection
of the physiological roles of NaV1.2 and NaV1.6 in neurons and help define the role of specific channels in disease
states. This unique selectivity profile provides a new approach to
potentially treat disorders of neuronal hyperexcitability by selectively
downregulating excitatory circuits
Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na<sub>V</sub>1.7 with Efficacy in Rodent Pain Models
We report on a novel series of aryl
sulfonamides that act as nanomolar
potent, isoform-selective inhibitors of the human sodium channel hNa<sub>V</sub>1.7. The optimization of these inhibitors is described. We
aimed to improve potency against hNa<sub>V</sub>1.7 while minimizing
off-target safety concerns and generated compound <b>3</b>.
This agent displayed significant analgesic effects in rodent models
of acute and inflammatory pain and demonstrated that binding to the
voltage sensor domain 4 site of Na<sub>V</sub>1.7 leads to an analgesic
effect <i>in vivo</i>. Our findings corroborate the importance
of hNa<sub>V</sub>1.7 as a drug target for the treatment of pain
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain
Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of <i>N</i>‑([1,2,4]Triazolo[4,3‑<i>a</i>]pyridin-3-yl)methane-sulfonamides as Potent and Selective <i>h</i>Na<sub>V</sub>1.7 Inhibitors for the Treatment of Pain
The
sodium channel Na<sub>V</sub>1.7 has emerged as a promising
target for the treatment of pain based on strong genetic validation
of its role in nociception. In recent years, a number of aryl and
acyl sulfonamides have been reported as potent inhibitors of Na<sub>V</sub>1.7, with high selectivity over the cardiac isoform Na<sub>V</sub>1.5. Herein, we report on the discovery of a novel series
of <i>N</i>-([1,2,4]triazolo[4,3-<i>a</i>]pyridin-3-yl)methanesulfonamides
as selective Na<sub>V</sub>1.7 inhibitors. Starting with the crystal
structure of an acyl sulfonamide, we rationalized that cyclization
to form a fused heterocycle would improve physicochemical properties,
in particular lipophilicity. Our design strategy focused on optimization
of potency for block of Na<sub>V</sub>1.7 and human metabolic stability.
Lead compounds <b>10</b>, <b>13</b> (GNE-131), and <b>25</b> showed excellent potency, good <i>in vitro</i> metabolic stability, and low <i>in vivo</i> clearance
in mouse, rat, and dog. Compound <b>13</b> also displayed excellent
efficacy in a transgenic mouse model of induced pain