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  • Design, synthesis and structure-activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs.

Design, synthesis and structure-activity relationship studies of novel and diverse cyclooxygenase-2 inhibitors as anti-inflammatory drugs.

Journal of enzyme inhibition and medicinal chemistry (2014-02-13)
Shigeo Hayashi, Naomi Ueno, Akio Murase, Junji Takada
ABSTRACT

Because of the pivotal role of cyclooxygenase (COX) in the inflammatory processes, non-steroidal anti-inflammatory drugs (NSAIDs) that suppress COX activities have been used clinically for the treatment of inflammatory diseases/syndromes; however, traditional NSAIDs exhibit serious side-effects such as gastrointestinal damage and hyper sensitivity owing to their COX-1 inhibition. Also, COX-2 inhibition-derived suppressive or preventive effects against initiation/proliferation/invasion/motility/recurrence/metastasis of various cancers/tumours such as colon, gastric, skin, lung, liver, pancreas, breast, prostate, cervical and ovarian cancers are significant. In this study, design, synthesis and structure-activity relationship (SAR) of various novel {2-[(2-, 3- and/or 4-substituted)-benzoyl, (bicyclic heterocycloalkanophenyl)carbonyl or cycloalkanecarbonyl]-(5- or 6-substituted)-1H-indol-3-yl}acetic acid analogues were investigated to seek and identify various chemotypes of potent and selective COX-2 inhibitors for the treatment of inflammatory diseases, resulting in the discovery of orally potent agents in the peripheral-inflammation model rats. The SARs and physicochemical properties for the analogues are described as significant findings. For graphical abstract: see Supplementary Material. ( www.informahealthcare.com/enz ).

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Benzene, JIS 300, ≥99.5%, for residue analysis
Sigma-Aldrich
Potassium hydroxide solution, 0.1 M in isopropanol
Sigma-Aldrich
Pyridine, JIS special grade, ≥99.5%
Sigma-Aldrich
N,N-Dimethylacetamide, SAJ first grade, ≥99.0%
Sigma-Aldrich
2-Propanol, JIS special grade, ≥99.5%
Sigma-Aldrich
Benzene, JIS special grade, ≥99.5%
Sigma-Aldrich
Hexane, JIS 300, ≥96.0%, for residue analysis
Sigma-Aldrich
Pyridine, suitable for hydroxyl value determination, ≥99.5%
Sigma-Aldrich
Ethyl acetate, JIS 300, ≥99.5%, for residue analysis
Sigma-Aldrich
Ethanol, ≥99.5%, SAJ super special grade
Sigma-Aldrich
Hexane, ≥96.0%, suitable for residual phthalate analysis
Sigma-Aldrich
Benzene, SAJ first grade, ≥99.0%
Sigma-Aldrich
Hexane, JIS 1000, ≥96.0%, for residue analysis
Sigma-Aldrich
Ethanol, JIS 1000, ≥99.5%, for residue analysis
Sigma-Aldrich
Ethyl acetate, JIS special grade, ≥99.5%
Sigma-Aldrich
Ethanol, ≥99.5%
Sigma-Aldrich
Potassium hydroxide solution, 1 M
Sigma-Aldrich
Pentane, SAJ special grade, ≥99.0%
Sigma-Aldrich
Potassium hydroxide solution, 0.5 M
Sigma-Aldrich
Pentane, SAJ first grade, ≥96.0%
Sigma-Aldrich
Butyl 4-hydroxybenzoate, SAJ first grade, ≥99.0%
Sigma-Aldrich
Dichloromethane, JIS special grade, ≥99.0%
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Hexane, SAJ first grade, ≥95.0%
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Dichloromethane, SAJ first grade, ≥99.0%
Sigma-Aldrich
Ethanol, JIS 300, ≥99.5%, for residue analysis
Sigma-Aldrich
Potassium hydroxide solution, 0.5 M in ethanol
Sigma-Aldrich
Bromine, SAJ first grade, ≥97.0%
Sigma-Aldrich
Potassium hydroxide solution, 0.02 M in ethanol
Sigma-Aldrich
Ethanol, ≥99.5%, suitable for absorption spectrum analysis
Sigma-Aldrich
Ethyl acetate, SAJ first grade, ≥99.0%