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
Discovery Chemistry, Discovery Research-Dr. Reddy's Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500 049, India.
Org Biomol Chem. 2004 Sep 7;2(17):2442-50. doi: 10.1039/B402787F. Epub 2004 Aug 11.
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 and the 4-NHMe-phenyl analog with a CF3, and the 4-OEt-phenyl analog 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 (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 was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.
设计、合成了在N1位具有新型药效团的1,5-二芳基吡唑类似物，并对其体外环氧化酶（COX-1/COX-2）抑制活性进行了评估。C-5苯环4位及其周围的变化，结合C-3位的CF3和CHF2基团，对COX-2抑制表现出高度的效力和选择性指数（SI）。这些强效化合物与一些早期化合物的体内评估表明，4-OMe-苯基类似物和带有CF3的4-NHMe-苯基类似物，以及在C-3位带有CHF2基团的4-OEt-苯基类似物，比塞来昔布具有更高的效力。除了具有令人印象深刻的抗炎、解热、镇痛和抗关节炎特性外，化合物（DRF-4367）还具有出色的药代动力学特征、长期关节炎研究中的胃肠道（GI）安全性以及人全血试验中的COX-2效力。因此，该化合物被选为用于临床前评估的口服活性抗炎候选药物。
