3-(2-Methoxytetrahydrofuran-2-yl)pyrazoles: a novel class of potent, selective cyclooxygenase-2 (COX-2) inhibitors (original) (raw)
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MedChemComm, 2018
With the aim of achieving new compounds possessing both anti-inflammatory and antiplatelet activities, we synthesized (E)-3-[3-(pyridin-3/4-yl)-1-(phenyl/sulfonylmethylphenyl)-1H-pyrazol-4-yl]acrylamides, and evaluated their COX-1 and COX-2 inhibitory and antiplatelet activities. Since COX-2 inhibitory and antiplatelet compounds have anticancer potential, we also screened their antiproliferative effects against three human cancer cell lines. Compounds 5n, 5p, 5s, 10d, 10g and 10i were determined as dual COX-2 inhibitor/antiplatelet compounds. Compound 10h appeared to be a compound that exhibited antiplatelet activity without inhibiting the COX enzyme. Compounds 5h, 10a and 10i were the most effective derivatives which displayed antiproliferative activity against Huh7, MCF7 and HCT116 cells. Particularly, compound 10i, as the compound exhibiting the highest cytotoxic, antiplatelet and COX-2 inhibitory activity, was remarkable.
Journal of Medicinal Chemistry, 1997
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structureactivity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC-236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
Bioorganic & medicinal chemistry, 2012
New pyrazole and pyrazoline derivatives have been synthesized and their ability to inhibit ovine COX-1/COX-2 isozymes was evaluated using in vitro cyclooxygenase (COX) inhibition assay. Among the tested compounds, N-((5-(4-chlorophenyl)-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)methylene)-3,5-bis(trifluoromethyl)aniline 8d exhibit optimal COX-2 inhibitory potency (IC(50)=0.26 lM) and selectivity (SI)=>192.3] comparable with reference drug celecoxib (IC(50) value of 0.28 lM and selectivity index of 178.57). Moreover, the anti-inflammatory activity of selected compounds, which are the most selective COX-2 inhibitors in the COX inhibition assay, was investigated in vivo using carrageenan-induced rat paw edema model. Molecular modeling was conducted to study the ability of the active compounds to bind into the active site of COX-2 which revealed a similar binding mode to SC-558, a selective COX-2 inhibitor.
ChemInform, 2005
First synthesis of novel 1,1-dioxo-2,3-dihydrobenzo[d]isothiazolyl substituted 1,5-diarylpyrazoles has been accomplished via oxidative cyclization of 4-nuoro-2-methyl benzenesulfonamide followed by the treatment with hydrazine and then with 1,3dicarbonyl compounds. A number of 1,5-diarylpyrazoles were synthesized in good yields and some of them were of potential biological interest. Cyclooxygenase-2 (COX-2) inhibitors are the topic of re'"cent research due to their antiinflammatory activity with reduced side effects of traditional NSAIDs at the gastrointestinal level (mucosal damage, bleeding) and less frequently, at the renal level. Most of the COX-2 inhibitors belong to the vicinal diary! heterocyclic class of compounds having an aminosulfonyl (S0 2 NH 2) or a methanesulfone (S0 2 Me) moiety attached to the p-position of one of the aryl ring. After the discovery of inducible isozyme (COX-2) in 1991, the methanesulfonanilide (NS398) and the diarylheterocycle (DUP-697) were first identified as non-ulcerogenic antiinflammatory agents (Fig. I) 1 • 2 • Subsequent research and rational drug design resulted in a number of potent and selective COX-2 inhibitors which validated the initial concept that a selective COX-2 inhibitor would illicit effective anti-inflammatory activity without the adverse ulcerogenic effect associated with the use of NSAIDs that inhibit both COX-I and COX-2. Accordingly celecoxib 3 and rofecoxib 4 followed by valdecoxib 5 and etoricoxib 6 became the first and second-generation selective COX-2 inhibitors (Fig. l) to enter the market. Celecoxib, a selective COX-2 inhibitor, belongs to a diary I heterocyclic class where two aryl moieties are attached to the adjacent positions of the central pyrazole ring. The 4benzenesulfonamide group attached to the nitrogen atom of the pyrazole ring is thought to be responsible for its efficacy and COX-2 selectivity in different models of inflammation. Recent study revealed that this class of compounds could be useful as dual COX-2/5-LO (5-lipooxygenase) inhibi-"'DRF Publication No. 340. toedicated to ProfessorS. M. Mukherji.
3,4-diarylpyrazoles: Potent and selective inhibitors of cyclooxygenase-2
Bioorganic & Medicinal Chemistry Letters, 1997
A series of 3,4-diarylpyrazoles was synthesized and evaluated lor their ability to selectively inhibit cyclooxygenase-2 (COX-2). A number of potent and selective inhibitors were identified and found to have oral anti-inflammatory activity in a rat carrageenan-induced foot pad edema assay. © 1997 Elsevier Science Ltd.
Journal of Medicinal Chemistry, 2003
A series of 1,5-diarylpyrazoles having a substituted benzenesulfonamide moiety as pharmacophore was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Through SAR and molecular modeling, it was found that fluorine substitution on the benzenesulfonamide moiety along with an electron-donating group at the 4-position of the 5-aryl ring yielded selectivity as well as potency for COX-2 inhibition in vitro. Among such compounds 3-fluoro-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide 3 displayed interesting pharmacokinetic properties along with antiinflammatory activity in vivo. Among the sodium salts tested in vivo, 10, the propionyl analogue of 3, showed excellent antiinflammatory activity and therefore represents a new lead structure for the development of injectable COX-2 specific inhibitors.
Journal of Chemistry
Series of diaryl-based pyrazole and triazole derivatives were designed and synthesized in a facile synthetic approach in order to produce selective COX-2 inhibitor. These series of derivatives were synthesized by different reactions like Vilsmeier–Haack reaction and click reaction. In vitro COX-1 and COX-2 inhibition studies showed that five compounds were potent and selective inhibitors of the COX-2 isozyme with IC50 values in 0.551–0.002 μM range. In the diarylpyrazole derivatives, compound 4b showed the best inhibitory activity against COX-2 with IC50 = 0.017 μM as one of the N-aromatic rings was substituted with sulfonamide and the other aromatic ring was unsubstituted. However, when the N-aromatic ring was substituted with sulfonamide and the other aromatic ring was substituted with sulfone (compound 4d), best COX-2 selectivity was achieved (IC50 = 0.098 μM, SI = 54.847). In the diaryltriazole derivatives, compound 15a showed the best inhibitory activity in comparison to all sy...
Synthesis of 1-P-SULF Am Ylphen YL-3 Trifluoromethylpyrazoles Class of CYCLOOXYGENASE-2 Inhibitors
Heterocyclic Communications, 2003
Condensation of p-sulfamylphenylhydrazine with diketones 1 afforded pyrazoles 2. Reaction of 2 with isocyanate and isothiocyanate derivatives gave the corresponding ureas 3 and thioureas 4 respectively. Cyclization of the thioureido group of compounds 4 by treating with ethyl bromoacetate, ethyl ß-bromopropionate and abromoacetophenone afforded the corresponding thiazolidinone, thiazinone and thiazoline derivatives 5 , 6 and 1 respectively. Introduction: A number of selective inhibitors of cyclooxygenase-2 (COX-2) were shown to possess anti-inflammatory activity with little or no gastric side effects 1 ' 2. To date, two distinct structural classes of molecules have been reported as selective 3 4 inhibitors of COX-2, NS-398 and L-745, 337 are members of methanes sulfonamide class of inhibitors, and DUF 647 , SC-57666, (SC-58125) I are few of the many examples of the tricyclic inhibitors class (Figure 1). 14 Recently, it was found that within the 1,5-diarylpyrazole class of COX-2 inhibitors, the p-sulfamylphenyl group was essential for good COX-2 inhibitors potency and in vivo efficacy. Also, although there was substantial flexibility in functionality allowed at the 3-position of the pyrazole, trifluoromethyl and difluoromethyl were optimal in terms of potency and selectivity. In addition, substituents on the phenyl moiety at 5-position of the pyrazole ring had profound effects on both in vitro potency and selectivity. Morover, CELEBRX Π is a nonsteroided anti-inflammatory drug that exhibits antiflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of CELEBREX is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2) and at therapeutic concentrations in humans. In continuation of our previous work 15 20 in the synthesis of trisubstituted pyrazoles containing trifluoromethyl and/or sulfonamide moieties, many new 1,5-diarylpyrazoles of selective COX-2 inhibitors related to the previously reported I and II were synthesised as a class of COX-2 inhbitors. Results and Discussion: Condensation of the key intermediate, p-sulfamylphenylhydrazine hydrochloride with fluorodiketones ! afforded 5-substituted-3-trifIuoromethyl-l-(p-sulfamylphenyl)pyrazoles (2; Table 1). The IR spectra of this pyrazoline displayed two absoption bands at 3225 cm' 1 and 3347 cm" 1 indicative of the NH2 group, in addition to two strong bands at 1335-1345 and 1152-1150 cm" 1 for the SO2N group. Their 'h NMR spectra exhibited the aromatic and the NH2 protons as multipiets at δ 6.52-8.14 (Tabel 2). Condensation of pyrazole derivatives 2 with the appropriate isocyanate and isothiocyanate in dry acetone yielded the corresponding benzenesulfonylurea 3 and thiourea 4 derivatives respectively (Table 1). The IR spectra of these compounds exhibited two bands at 1330-1350 cm 1 and 1150-1165 cm 1 due to SO2N group as well as a urea carbonyl band at 1650-1656 cm 1 in the case of compounds 3 and a thiourea carbonyl absorption at 1136-1140 cm 1 in the case of compounds 4. The structure of the above compounds 3 and 4 were further supported by their elemental analyses as well as 'h NMR spectra (Table 2).