Synthesis and pharmacological evaluation of novel N-aryl-3,4-dihydro-1′H-spiro[chromene-2,4′-piperidine]-1′-carboxamides as TRPM8 antagonists
| Autor: | Dinesh Pradeep Wale, Anupindi Raghuram, Shobha S. Rao, Indranil Mukhopadhyay, Neelima Khairatkar-Joshi, Sachin Sundarlal Chaudhari, Pallavi V. Karnik, Thamil Selvan Vaiyapuri, Ashok Bhausaheb Kadam, A. P. Thomas, Ramchandra R. Sangana, Girish S. Gudi, Vikram Mansingh Bhosale |
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| Rok vydání: | 2013 |
| Předmět: |
Male
Stereochemistry Clinical Biochemistry Administration Oral TRPM Cation Channels Pharmaceutical Science Ring (chemistry) Biochemistry Rats Sprague-Dawley Mice Structure-Activity Relationship chemistry.chemical_compound Piperidines Pharmacokinetics Drug Discovery Animals Potency Spiro Compounds Channel blocker Molecular Biology Analgesics Aryl Organic Chemistry Rational design Stereoisomerism Amides Rats Mice Inbred C57BL Disease Models Animal chemistry Neuralgia Molecular Medicine Piperidine Selectivity Half-Life Protein Binding |
| Zdroj: | Bioorganic & Medicinal Chemistry. 21:6542-6553 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2013.08.031 |
| Popis: | A novel series of N -aryl-3,4-dihydro-1′ H -spiro[chromene-2,4′-piperidine]-1′-carboxamides was identified as transient receptor potential melastatin 8 (TRPM8) channel blockers through analogue-based rational design, synthesis and screening. Details of the synthesis, effect of aryl groups and their substituents on in-vitro potency were studied. The effects of selected functional groups on the 4-position of the chromene ring were also studied, which showed interesting results. The 4-hydroxy derivatives showed excellent potency and selectivity. Optical resolution and screening of alcohols revealed that ( R )-(–)-isomers were in general more potent than the corresponding ( S )-(+)-isomers. The isomer ( R )-(–)- 10e (IC 50 : 8.9 nM) showed a good pharmacokinetic profile upon oral dosing at 10 mg/kg in Sprague–Dawley (SD) rats. The compound ( R )-(–)- 10e also showed excellent efficacy in relevant rodent models of neuropathic pain. |
| Databáze: | OpenAIRE |
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