6-Alkyl, alkoxy, or alkylthio-substituted 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors

Rao, P Narasimha; Amini, Mohsen; Li, Huiying; Habeeb, Amgad G.; Knaus, Edward E.

doi:10.1016/s0960-894x(03)00391-3

Cited by 41 publications

(6 citation statements)

References 16 publications

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“…Since the discovery and characterization of COX-2 isozyme, more than a thousand of its inhibitors have been reported in the literature with structural diversity [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]. Now, at least two molecules (celecoxib and rofecoxib) are in clinical use as anti-inflammatory and analgesic drugs.…”

Section: Introductionmentioning

confidence: 99%

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

Park

Lee

2005

J Comput Aided Mol Des

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The discovery of selective cyclooxygenase-2 (COX-2) inhibitors represents a major achievement of the efforts over the past few decades to develop therapeutic treatments for inflammation. To gain insights into designing new COX-2-selective inhibitors, we address the energetic and structural basis for the selective inhibition of COX isozymes by means of a combined computational protocol involving docking experiment, force field design for the heme prothetic group, and free energy perturbation (FEP) simulation. We consider both COX-2- and COX-1-selective inhibitors taking the V523I mutant of COX-2 to be a relevant structural model for COX-1 as confirmed by a variety of experimental and theoretical evidences. For all COX-2-selective inhibitors under consideration, we find that free energies of binding become less favorable as the receptor changes from COX-2 to COX-1, due to the weakening and/or loss of hydrogen bond and hydrophobic interactions that stabilize the inhibitors in the COX-2 active site. On the other hand, COX-1-selective oxicam inhibitors gain extra stabilization energy with the change of residue 523 from valine to isoleucine because of the formations of new hydrogen bonds in the enzyme-inhibitor complexes. The utility of the combined computational approach, as a valuable tool for in silico screening of COX-2-selective inhibitors, is further exemplified by identifying the physicochemical origins of the enantiospecific selective inhibition of COX-2 by alpha-substituted indomethacin ethanolamide inhibitors.

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Section: Introductionmentioning

confidence: 99%

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

Park

Lee

2005

J Comput Aided Mol Des

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“…In an earlier communication, we attributed the excellent in vitro COX-2 inhibitory activity exhibited by 14s to the presence of a weak hydrogen bonding interaction of the sulfur atom of the C-6 thioethyl (SEt) substituent with the O H of Ser 530 in the COX-2 binding site . A recent molecular modeling study has confirmed the importance of Ser 530 in the COX-2 inhibitory potency of diarylheterocyclic COX-2 inhibitors .…”

Section: Resultsmentioning

confidence: 97%

“…All these tricyclic molecules possess 1,2-diaryl substitution on a central four-, five-, or six-membered ring system such as cyclobutenone ( 3 ), cyclopentene ( 4 ), isoxazole ( 5 ), pyrazole ( 1 ), 2-(5 H )-furanone ( 2 ), or pyridine ( 6 ), respectively (Chart ). ,− Structure−activity relationship (SAR) studies have shown that for optimum COX-2 selectivity and inhibitory potency, a SO 2 Me or SO 2 NH 2 substituent at the para - position of a phenyl ring, and that the presence of a p -F substituent on the nonsulfonyl vicinal phenyl ring improves in vivo activity . In a very recent letter, we reported the design and synthesis of a novel class of diarylheterocycle with a central six-membered lactone (pyran-2-one) ring which exhibited good in vitro COX-2 inhibitory potency and selectivity . The Merck Co. has also developed novel methods to synthesize diarylheterocycles having a central six-membered lactone (pyran-2-one) ring system .…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of 6-Substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: A Novel Class of Diarylheterocyclic Selective Cyclooxygenase-2 Inhibitors

Rao

Amini

et al. 2003

J. Med. Chem.

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A group of 6-alkyl (alkoxy or alkylthio)-4-aryl-3-(4-methanesulfonylphenyl)pyran-2-ones (14a-v), possessing either a H or F substituent at the para-position of the C-4 phenyl ring, were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors with in vivo antiinflammatory-analgesic activities. Although 6-ethylthio-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14s) exhibited a very high in vitro COX-2 inhibitory potency (IC(50) = 0.0032 muM) and COX-2 selectivity (SI > 120 000), 14s exhibited moderate antiinflammatory activity compared to celecoxib in a carrageenan-induced rat paw edema assay. In contrast, the less potent (IC(50) = 0.10 muM), and less selective (SI = 2880) COX-2 inhibitor 6-ethoxy-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (14i) exhibited good antiinflammatory activity where a 1 mg/kg oral dose reduced inflammation 32 and 67% at 3 and 5 h postdrug administration relative to the reference drug celecoxib where a 50 mg/kg oral dose reduced inflammation by 79 and 58% at the respective 3 and 5 h time periods. Molecular modeling studies, where 14i was docked in the active site of both COX-1 and COX-2, reveals that the C-6 ethoxy substituent orients the pyran-2-one ring to position the SO(2)Me pharmacophore in the vicinity of the secondary pocket in COX-2. The absence of this COX-2 secondary pocket in the COX-1 binding site is due to the presence of the bulky Ile(523) in COX-1 such that access to the amino acid residues (Ile(517), Phe(518), Gln(192), and His(90)), which line the COX-2 secondary pocket with which the SO(2)Me pharmacophore could interact, is hindered. The six-membered pyran-2-one ring system is a suitable central template to design selective COX-2 inhibitors.

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“…Bioassay Procedures. Determination of free-radical DPPH scavenging and xanthine oxidase activity was done as per the method described earlier …”

Section: Methodsmentioning

confidence: 99%

Free-Radical-Scavenging and Xanthine Oxidase Inhibitory Constituents from Stereospermum personatum

et al. 2005

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Bioassay-guided fractionation of different extracts of both stem and stem bark of Stereospermum personatum led to the isolation of free-radical-scavenging and xanthine oxidase inhibitory molecules along with three new anthraquinones, sterequinones F-H (1-3), a new naphthoquinone, sterequinone I (4), two new phenethyl esters, 2(4'-hydroxyphenyl)ethyl undecanoate (14) and 2(4'-hydroxyphenyl)ethyl nonacosanoate (15), and a new 3,4,5-trimethoxycinnamyl ether, 2-methoxy-4-[3'-(3'',4'',5''trimethoxyphenyl)allyloxymethyl]phenol (16), together with known compounds. The antioxidant and xanthine oxidase inhibitory potentials of the isolated compounds are reported.

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6-Alkyl, alkoxy, or alkylthio-substituted 3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: a novel class of diarylheterocyclic selective cyclooxygenase-2 inhibitors

Cited by 41 publications

References 16 publications

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

Free energy perturbation approach to the critical assessment of selective cyclooxygenase-2 inhibitors

Design, Synthesis, and Biological Evaluation of 6-Substituted-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-ones: A Novel Class of Diarylheterocyclic Selective Cyclooxygenase-2 Inhibitors

Free-Radical-Scavenging and Xanthine Oxidase Inhibitory Constituents from Stereospermum personatum

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