Abstract
After extensive synthetic efforts, we found that many structurally diverse bioisosteres could be generated via derivatizing the C-4 alkyl chain on the pyrazole ring of compound 3 (B/P = 1/33) with different electronegative groups. Especially when a sulfonamide or sulfamide moiety was added, resulting compounds exhibited not only potent CB1R activity but also a desired tPSA value over 90 Å(2), a threshold considered to possess a low probability to cross BBB, leading to the identification of compound 4 (B/P = 1/64) as a peripherally restricted CB1R antagonist. Apart from its significant weight-loss efficacy in DIO mice, compound 4 also displays 163 clean off-target profiles and is currently under development for treating obesity and the related metabolic syndrome.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Diet, High-Fat / adverse effects*
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Discovery*
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Mice
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Mice, Inbred C57BL
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Mice, Obese
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Molecular Structure
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Obesity / drug therapy*
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Pyrazoles / administration & dosage
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrazoles / therapeutic use
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Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
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Solubility
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Sulfonamides / administration & dosage
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
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Sulfonamides / therapeutic use
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Weight Loss / drug effects*
Substances
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1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl)phenyl)ethynyl)thiophene-2-yl)-1H-pyrazole-3-carboxamide
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Pyrazoles
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Receptor, Cannabinoid, CB1
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Sulfonamides