8 research outputs found
Design and Synthesis of a Pan-Janus Kinase Inhibitor Clinical Candidate (PF-06263276) Suitable for Inhaled and Topical Delivery for the Treatment of Inflammatory Diseases of the Lungs and Skin
Get PDFBy use of a structure-based computational method for identification of structurally novel Janus kinase (JAK) inhibitors predicted to bind beyond the ATP binding site, a potent series of indazoles was identified as selective pan-JAK inhibitors with a type 1.5 binding mode. Optimization of the series for potency and increased duration of action commensurate with inhaled or topical delivery resulted in potent pan-JAK inhibitor 2 (PF-06263276), which was advanced into clinical studies
Practical One‐Pot Procedure for the Synthesis of 1,2,3,4‐Tetrahydroquinolines by the Imino‐Diels‐Alder Reaction
No full textQuantifying the A1AR distribution in peritumoural zones around experimental F98 and C6 rat brain tumours
No full textDiscovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of Na<sub>V</sub>1.7 with Efficacy in Rodent Pain Models
No full textWe 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
No full textThe
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
No full textThe
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
No full textThe
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
