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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

Supelco
Acetic acid, analytical standard
Supelco
Hydrogen chloride – 2-propanol solution, ~1.25 M HCl (T), for GC derivatization, LiChropur
Sigma-Aldrich
Sodium chloride, BioUltra, for molecular biology, ≥99.5% (AT)
Supelco
Hydrogen chloride – ethanol solution, ~1.25 M HCl, for GC derivatization, LiChropur
Supelco
Hydrogen chloride – methanol solution, ~1.25 m HCl (T), for GC derivatization, LiChropur
Supelco
N,N-Dimethylformamide, analytical standard
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Methanol, analytical standard
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Diethyl ether, analytical standard
Supelco
Acetone, analytical standard
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Chloroform, analytical standard
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Tetrahydrofuran, Selectophore, ≥99.5%
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Tetrahydrofuran, analytical standard
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Sodium chloride solution, 0.85%
Supelco
Water, suitable for ion chromatography
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Ethanol solution, certified reference material, 2000 μg/mL in methanol
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3-Ethyl-2,4-pentanedione, mixture of tautomers, 98%
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Water, deuterium-depleted, ≤1 ppm (Deuterium oxide)
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Water, for HPCE, for luminescence, suitable for UV/Vis spectroscopy
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Citrate Concentrated Solution, BioUltra, for molecular biology, 1 M in H2O
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Cyclohexanecarbonyl chloride, 98%
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Water, tested according to Ph. Eur.
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Sodium hydroxide, BioUltra, for luminescence, ≥98.0% (T), pellets
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Water, for cell biology, sterile ultrafiltered
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Benzenesulfonyl chloride, for HPLC derivatization
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Water, for molecular biology, sterile filtered
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Sodium chloride, random crystals, optical grade, 99.9% trace metals basis
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o-Toluoyl chloride, 99%
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1,8-Diazabicyclo[5.4.0]undec-7-ene, 98%
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Ammonium chloride, 99.998% trace metals basis
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Diethyl ether