1423161-91-4

Upstream product

• 640280-28-0 1-bromo-2-iodo-4-(trifluoromethyl)benzene 
• 847818-74-0 1-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole 
• 57946-63-1 4-amino-3-bromobenzotrifluoride 
• 175135-49-6 N-(2-bromo-4-(trifluoromethyl)phenyl)acetamide 
• 1423162-02-0 2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)aniline 

Downstream Products

• 1423161-92-5 (2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)boronic acid 
• 1423161-87-8 perfluorophenyl 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-indole-6-sulfonate 
• 1423161-99-2 tert-butyl 6-((2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate 
• 1423162-00-8 N-(2,4-dimethoxybenzyl)-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-pyrrolo[2,3-b]pyridine-6-sulfonamide 
• 1423160-80-8 C₂₄H₂₁F₃N₆O₂S₂ 
• 1423160-82-0 C₂₃H₁₇F₃N₆O₃S₂ 
• 1423160-90-0 1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide 
• 1423160-96-6 C₂₃H₁₈F₃N₅O₂S₂ 
• 1423161-12-9 C₂₅H₁₉F₆N₅O₂S₂ 
• 1423161-22-1 C₂₀H₁₄F₃N₇O₂S₂ 
• 1454666-21-7 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide 
• 1454667-32-3 5-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline 

Relevant academic research and scientific papers

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

SULFONAMIDE COMPOUNDS AS VOLTAGE-GATED SODIUM CHANNEL MODULATORS

The present invention relates to sulfonamide compounds Formula (I) wherein the substituents are as described herein, and their use in a medicine for the treatment of diseases, disorders associated with the inhibition of Voltage-gated sodium channels (VGSC) particularly NaV1.7. It further relates to the compounds herein and their pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof useful in treating diseases, disorders, syndromes and/or conditions associated with the inhibition of Voltage-gated sodium channels (VGSC) particularly NaV1.7. The invention also relates to process for the preparation of the compounds of the invention. (I)

Sulfonamides as Selective NaV1.7 Inhibitors: Optimizing Potency and Pharmacokinetics to Enable in Vivo Target Engagement

Human genetic evidence has identified the voltage-gated sodium channel NaV1.7 as an attractive target for the treatment of pain. We initially identified naphthalene sulfonamide 3 as a potent and selective inhibitor of NaV1.7. Optimization to reduce biliary clearance by balancing hydrophilicity and hydrophobicity (Log D) while maintaining NaV1.7 potency led to the identification of quinazoline 16 (AM-2099). Compound 16 demonstrated a favorable pharmacokinetic profile in rat and dog and demonstrated dose-dependent reduction of histamine-induced scratching bouts in a mouse behavioral model following oral dosing.

HETEROARYL SODIUM CHANNEL INHIBITORS

The present invention provides compounds of Formula I or II, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.

SULFAMIDE SODIUM CHANNEL INHIBITORS

The present invention provides compounds of Formula I, or pharmaceutically acceptable salts thereof, that are inhibitors of voltage-gated sodium channels, in particular Nav 1.7. The compounds are useful for the treatment of diseases treatable by inhibition of sodium channels such as pain disorders. Also provided are pharmaceutical compositions containing compounds of the present invention.