- 2-Hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl] -1-benzenesulfonamide (DRF-4367): An orally active COX-2 inhibitor identified through pharmacophoric modulation
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Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog 6 and the 4-NHMe-phenyl analog 9 with a CF3, and the 4-OEt-phenyl analog 19 with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound 6 (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound 6 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.
- Singh, Sunil Kumar,Vobbalareddy, Saibaba,Kalleda, Srinivasa Rao,Rajjak, Shaikh Abdul,Casturi, Seshagiri Rao,Datla, Srinivasa Raju,Mamidi, Rao N.V.S.,Mullangi, Ramesh,Bhamidipati, Ravikanth,Ramanujam, Rajagopalan,Akella, Venkateswarlu,Yeleswarapu, Koteswar Rao
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p. 2442 - 2450
(2007/10/03)
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- FLUORINE CONTAINING BIOACTIVE HETEROCYCLES PART III : SYNTHESIS OF SOME NEW FLUORINE CONTAINING PHENYLGLYOXALS AND 1,2,4-TRIAZINE DERIVATIVES
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Some medicinally important new fluorine containing phenylglyoxals have been synthesized by selenium dioxide oxidation of appropriate fluorinated acetophenones and characterized by spectrum studies.The phenylglyoxals were treated with thiosemicarbazide to give corresponding thiosemicarbazones (III) which were cyclized, in situ, to yield 5-(fluorophenyl)-1,2,4-triazine-3(2H)-thiones.The 5-(4-fluorophenyl)-1,2,4-triazine-3-(2H)-thione (IV) undergoes nucleophilic displacement when refluxed with hydrazine hydrate to give corresponding 3-hydrazino-5-(4-fluorophenyl)-1,2,4-tria zine.The hydrazino derivative reacts with fluorinated 1,3-diketones, in glacial acetic acid yielding 5-(4-fluorophenyl)-3--1,2,4-triazines (VII).All synthesized compounds have been characterized on the basis of elemental analyses, ir, pmr and 19F nmr studies.
- Joshi, Krishna C.,Dubey, Kalpana,Dandia, Anshu
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p. 1545 - 1553
(2007/10/02)
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