Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template

• Published in: Biochemical and biophysical research communications 2003-01, Vol.301 (1), p.183-186
• Main Authors: Pillai, Ajay D, Rathod, Parendu D, P.X, Franklin, Patel, Manoj, Nivsarkar, Manish, Vasu, Kamala K, Padh, Harish, Sudarsanam, Vasudevan
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemical synthesis; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - therapeutic use; Carrageenin; Chronic model; Cyclooxygenase Inhibitors - chemical synthesis; Cyclooxygenase Inhibitors - chemistry; Cyclooxygenase Inhibitors - therapeutic use; Disease Models, Animal; Drug Design; Edema - chemically induced; Edema - drug therapy; Formaldehyde - toxicity; Inflammation - chemically induced; Inflammation - drug therapy; Molecular Structure; Pyridines - chemistry; Rats; Thiophene; Thiophenes - chemical synthesis; Thiophenes - chemistry; Thiophenes - therapeutic use
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/S0006-291X(02)02996-0

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.