Sultan Chowdhury

Discovery of Aryl Sulfonamides as Isoform-Selective Inhibitors of NaV1.7 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 hNaV1.7. The optimization of these inhibitors is described. We aimed to improve potency against hNaV1.7 while minimizing off-target safety concerns and generated compound 3. 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 NaV1.7 leads to an analgesic effect in vivo. Our findings corroborate the importance of hNaV1.7 as a drug target for the treatment of pain.

The discovery of benzenesulfonamide-based potent and selective inhibitors of voltage-gated sodium channel Na v 1.7

The voltage gated sodium channel Nav1.7 represents an interesting target for the treatment of pain. Human genetic studies have identified the crucial role of Nav1.7 in pain signaling. Herein, we report the design and synthesis of a novel series of benzenesulfonamide-based Nav1.7 inhibitors. Structural-activity relationship (SAR) studies were undertaken towards improving Nav1.7 activity and minimizing CYP inhibition. These efforts resulted in the identification of compound 12k, a highly potent Nav1.7 inhibitor with a thousand-fold selectivity over Nav1.5 and negligible CYP inhibition.

Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic Syndrome

Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC(50) = 14 nM and HepG2 IC(50) = 12 nM) and efficacious in vivo (ED(50) = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.

Tetracyclic spirooxindole blockers of hNaV1.7: activity in vitro and in CFA-induced inflammatory pain model

The structure–activity relationship of a new series of tetracyclic spirooxindoles led to the discovery of compound 25a, a potent hNaV1.7 blocker with improved ADME properties and in vivo efficacy in the CFA-induced inflammatory pain model.

Discovery of benzylisothioureas as potent divalent metal transporter 1 (DMT1) inhibitors

Inhibition of intestinal brush border DMT1 offers a novel therapeutic approach to the prevention and treatment of disorders of iron overload. Several series of diaryl and tricyclic benzylisothiourea compounds as novel and potent DMT1 inhibitors were discovered from the original hit compound 1. These compounds demonstrated in vitro potency against DMT1, desirable cell permeability properties and a dose-dependent inhibition of iron uptake in an acute rat model of iron hyperabsorption. Tricyclic compounds increased the in vitro potency by up to 16-fold versus the original hit. Diaryl compounds 6b and 14a demonstrated significant iron absorption inhibition in vivo with both 25 and 50 mg/kg doses. The diaryl and tricyclic compounds described in this report represent promising structural templates for further optimization.

Systematic evaluation of amide bioisosteres leading to the discovery of novel and potent thiazolylimidazolidinone inhibitors of SCD1 for the treatment of metabolic diseases

Several five- and six-membered heterocycles were introduced to replace the C2-position amide bond of the original 2-aminothiazole-based hit compound 5. Specifically, replacement of the amide bond with an imidazolidinone moiety yielded a novel and potent thiazolylimidazolidinone series of SCD1 inhibitors. XEN723 (compound 22) was identified after optimization of the thiazolylimidazolidinone series. This compound demonstrated a 560-fold improvement in in vitro potency and reduced plasma desaturation indices in a dose dependent manner, with an EC50 of 4.5 mg/kg.

Discovery of triazolone derivatives as novel, potent stearoyl-CoA desaturase-1 (SCD1) inhibitors.

Stearoyl-CoA desaturase-1 (SCD1) plays an important role in lipid metabolism. Inhibition of SCD1 activity represents a potential novel approach for the treatment of metabolic diseases such as obesity, type 2 diabetes and dyslipidemia, as well as skin diseases, acne and cancer. Herein, we report the synthesis and structure-activity relationships (SAR) of a series of novel triazolone derivatives, culminating in the identification of pyrazolyltriazolone 17a, a potent SCD1 inhibitor, which reduced plasma C16:1/C16:0 triglycerides desaturation index (DI) in an acute Lewis rat model in a dose dependent manner, with an ED50 of 4.6 mg/kg. In preliminary safety studies, compound 17a did not demonstrate adverse effects related to SCD1 inhibition after repeat dosing at 100mg/kg. Together, these data suggest that sufficient safety margins can be achieved with certain SCD1 inhibitors, thus allowing exploration of clinical utility in metabolic disease settings.

Design of Conformationally Constrained Acyl Sulfonamide Isosteres: Identification of N-([1,2,4]Triazolo[4,3-a]pyridin-3-yl)methane-sulfonamides as Potent and Selective hNaV1.7 Inhibitors for the Treatment of Pain

The sodium channel NaV1.7 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 NaV1.7, with high selectivity over the cardiac isoform NaV1.5. Herein, we report on the discovery of a novel series of N-([1,2,4]triazolo[4,3- a]pyridin-3-yl)methanesulfonamides as selective NaV1.7 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 NaV1.7 and human metabolic stability. Lead compounds 10, 13 (GNE-131), and 25 showed excellent potency, good in vitro metabolic stability, and low in vivo clearance in mouse, rat, and dog. Compound 13 also displayed excellent efficacy in a transgenic mouse model of induced pain.

Selective NaV1.7 Antagonists with Long Residence Time Show Improved Efficacy against Inflammatory and Neuropathic Pain

Selective block of NaV1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several NaV1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma.