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Start Over Author "Nigade PB" Publisher american chemical society
2 results on '"Nigade PB"'

1. Discovery of Potent, Selective, and State-Dependent Na V 1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Author

Ramdas V, Talwar R, Kanoje V, Loriya RM, Banerjee M, Patil P, Joshi AA, Datrange L, Das AK, Walke DS, Kalhapure V, Khan T, Gote G, Dhayagude U, Deshpande S, Shaikh J, Chaure G, Pal RR, Parkale S, Suravase S, Bhoskar S, Gupta RV, Kalia A, Yeshodharan R, Azhar M, Daler J, Mali V, Sharma G, Kishore A, Vyawahare R, Agarwal G, Pareek H, Budhe S, Nayak A, Warude D, Gupta PK, Joshi P, Joshi S, Darekar S, Pandey D, Wagh A, Nigade PB, Mehta M, Patil V, Modi D, Pawar S, Verma M, Singh M, Das S, Gundu J, Nemmani K, Bock MG, Sharma S, Bakhle D, Kamboj RK, and Palle VP

Subjects
Animals, Chromans pharmacokinetics, Chromans therapeutic use, Cytochrome P-450 CYP2C9 chemistry, Cytochrome P-450 CYP2C9 metabolism, Cytochrome P-450 CYP3A chemistry, Cytochrome P-450 CYP3A metabolism, Disease Models, Animal, Drug Design, Drug Evaluation, Preclinical, Half-Life, Male, Mice, Mice, Inbred BALB C, NAV1.7 Voltage-Gated Sodium Channel chemistry, Neuralgia chemically induced, Neuralgia drug therapy, Neuralgia pathology, Protein Isoforms antagonists & inhibitors, Protein Isoforms metabolism, Structure-Activity Relationship, Sulfonamides pharmacokinetics, Sulfonamides therapeutic use, Voltage-Gated Sodium Channel Blockers pharmacokinetics, Voltage-Gated Sodium Channel Blockers therapeutic use, Chromans chemistry, NAV1.7 Voltage-Gated Sodium Channel metabolism, Sulfonamides chemistry, Voltage-Gated Sodium Channel Blockers chemistry
Abstract

Voltage-gated sodium channel Na V 1.7 is a genetically validated target for pain. Identification of Na V 1.7 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 Na V 1.7 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 Na V 1.5, 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.

Published
2020
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2. Discovery of Novel, Potent, Brain-Permeable, and Orally Efficacious Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptor [4-(5-(4-Chlorophenyl)-4-methyl-2-propionylthiophen-3-yl)benzenesulfonamide]: Structure-Activity Relationship and Preclinical Characterization.

Author

Sinha N, Karche NP, Verma MK, Walunj SS, Nigade PB, Jana G, Kurhade SP, Hajare AK, Tilekar AR, Jadhav GR, Thube BR, Shaikh JS, Balgude S, Singh LB, Mahimane V, Adurkar SK, Hatnapure G, Raje F, Bhosale Y, Bhanage D, Sachchidanand S, Dixit R, Gupta R, Bokare AM, Dandekar M, Bharne A, Chatterjee M, Desai S, Koul S, Modi D, Mehta M, Patil V, Singh M, Gundu J, Goel RN, Shah C, Sharma S, Bakhle D, Kamboj RK, and Palle VP

Subjects
Alzheimer Disease drug therapy, Animals, Brain metabolism, Clinical Trials as Topic, Drug Stability, Humans, Male, Molecular Structure, Nicotinic Agonists chemical synthesis, Nicotinic Agonists pharmacokinetics, Nootropic Agents chemical synthesis, Nootropic Agents pharmacokinetics, Rats, Sprague-Dawley, Rats, Wistar, Structure-Activity Relationship, Sulfonamides chemical synthesis, Sulfonamides pharmacokinetics, Thiophenes chemical synthesis, Thiophenes pharmacokinetics, Drug Discovery, Nicotinic Agonists pharmacology, Nootropic Agents pharmacology, Sulfonamides pharmacology, Thiophenes pharmacology, alpha7 Nicotinic Acetylcholine Receptor agonists
Abstract

The discovery of a series of thiophenephenylsulfonamides as positive allosteric modulators (PAM) of α7 nicotinic acetylcholine receptor (α7 nAChR) is described. Optimization of this series led to identification of compound 28, a novel PAM of α7 nicotinic acetylcholine receptor (α7 nAChR). Compound 28 showed good in vitro potency, with pharmacokinetic profile across species with excellent brain penetration and residence time. Compound 28 robustly reversed the cognitive deficits in episodic/working memory in both time-delay and scopolamine-induced amnesia paradigms in the novel object and social recognition tasks, at very low dose levels. Additionally, compound 28 has shown excellent safety profile in phase 1 clinical trials and is being evaluated for efficacy and safety as monotherapy in patients with mild to moderate Alzheimer's disease.

Published
2020
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