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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

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Ethyl acetate, ReagentPlus®, ≥99.8%
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Pyridine, ≥99%
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Diethyl malonate, ReagentPlus®, 99%
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N,N-Dimethylacetamide, ReagentPlus®, ≥99%
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n-Butyllithium solution, 2.5 M in hexanes
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Tetrabutylammonium tribromide, 98%
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2-Propanol, anhydrous, 99.5%
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Potassium carbonate, 99.995% trace metals basis
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Butyl 4-hydroxybenzoate, ≥99%
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Dichloromethane, anhydrous, ≥99.8%, contains 40-150 ppm amylene as stabilizer
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Pentane, anhydrous, ≥99%
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Pyridine, anhydrous, 99.8%
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N,N-Dimethylacetamide, anhydrous, 99.8%
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Magnesium sulfate, ≥99.99% trace metals basis
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Ethyl acetate, anhydrous, 99.8%
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Sodium bicarbonate-12C, 99.9 atom % 12C
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6-Chloroindole, 99%
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Potassium hydroxide, tested according to Ph. Eur.
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Trifluoroacetic acid, analytical standard
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5α-Androstan-17β-ol-3-one, purum, ≥99.0% (TLC)
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