6 research outputs found
Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
A novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound <b>3</b>, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of <b>24</b>, a highly potent and selective inhibitor of PI3Kδ
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
Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
PI3Kδ is a lipid kinase and a member of a larger
family of enzymes, PI3K class IA(α, β, δ) and IB
(γ), which catalyze the phosphorylation of PIP2 to PIP3. PI3Kδ
is mainly expressed in leukocytes, where it plays a critical, nonredundant
role in B cell receptor mediated signaling and provides an attractive
opportunity to treat diseases where B cell activity is essential,
e.g., rheumatoid arthritis. We report the discovery of novel, potent,
and selective PI3Kδ inhibitors and describe a structural hypothesis
for isoform (α, β, γ) selectivity gained from interactions
in the affinity pocket. The critical component of our initial pharmacophore
for isoform selectivity was strongly associated with CYP3A4 time-dependent
inhibition (TDI). We describe a variety of strategies and methods
for monitoring and attenuating TDI. Ultimately, a structure-based
design approach was employed to identify a suitable structural replacement
for further optimization