1,2-Diarylcyclopentenes as Selective Cyclooxygenase-2 Inhibitors and Orally Active Anti-inflammatory Agents

Abstract

A series of 1,2-diarylcyclopentene methyl sulfones and sulfonamides have been shown to be remarkably potent and selective cyclooxygenase-2 (COX-2) inhibitors. The methyl sulfone analogs 7 showed excellent COX-2 activity, with IC50s ranging from 0.003 (7f,n) to 0.87 (7o) microM. In addition, most analogs of 7 showed no activity (IC50 > 100 microM) against the COX-1 enzyme. Replacement of the methyl sulfone moiety with a sulfonamide group gave a slightly more potent (typically 2-5-fold) but less selective COX-2 inhibitor, mainly due to an increase (20- > 100-fold) in COX-1 activity. However, in vitro COX-1/COX-2 selectivity for the sulfonamides 8 could be increased in many cases by simply incorporating a substituent at the 3-position of the phenyl group. Furthermore, in vitro selectivity increased with the size and number of substituents, as demonstrated in the selectivity trend of 8k (8000) > 8j (1900) > 8i (500) > 8h (100). More importantly, the sulfonamide COX-2 inhibitors showed greatly enhanced oral activity in the rat model of established adjuvant-induced arthritis, with inhibition values of 79.0% (8a), 81.5% (8c), and 83.0% (8g) at 1 mg/kg. On the basis of its overall biological profile, sulfonamide 8c was evaluated as a potential clinical candidate, displaying an ED50 of 22 mpk in the rat carrageenan-induced paw edema model and an ED50 of 0.16 mpk in the rat established adjuvant-induced arthritis model with no indication of gastrointestinal toxicity in rats and mice at 200 mpk. In addition, a preparative-scale synthetic route to sulfonamide 8c has been developed.

Synthesis and evaluation of sulfonamide-bearing thiazole as carbonic anhydrase isoforms hCA I and hCA II

“…The importance of sulfonamide compounds in medicinal chemistry cannot be ignored and the compounds are wellknown pharmaceutical agents and have gained much attention due to their diverse biological activities in pharmaceutical as well as in agricultural areas 20 . The sulfonamide compounds have a number of biological activities, such as antibacterial 21 , antiinflammatory 22 , antitumor 23 , anticancer 24 and carbonic anhydrase inhibitory functions 25 . Carbonic anhydrase inhibitors or activators have many medical applications, such as in the treatment of glaucoma, in the management of neurological disorders, in the treatment of Alzheimer's disease.…”

7-(2,4-Dichlorophenyl)-2-methylsulfanylpyrazolo[1,5-a]pyrimidine-3-carbonitrile

“…For the biological activity of pyrazolo [1,5-a]pyrimidine derivatives, see: Li et al (1995). For applications of enaminones, see: El-Taweei et al (2001); Hernandez et al (2003); Olivera et al (2000).…”

“…Data collection: SMART (Bruker, 1998); cell refinement: SAINT (Bruker, 1999) (Li et al, 1995). Enaminones have been widely used as building blocks in the synthesis of pyrazolo[1,5-a]pyrimidine derivatives (El-Taweei et al, 2001;Hernandez et al, 2003;Olivera et al, 2000).…”

Design, synthesis, spectral characterization and bioactivity evaluation of new sulfonamide and carbamate derivatives of 5-Nitro-1H-indazole

“…Sulfonamide derivatives are an important class of drugs (-SO 2 -N-) which are bacteriostatic agents and find use in both human therapy and animal husbandry. 16 Sulfonamides exhibit different types of pharmacological activities such as antitumor, 17 hypoglycemic, 18 antithyroid, 19 anticarbonicanhydrase, 20 anti-inflammatory, 21 diuretic, 22 COX inhibitors, the enzyme dihydropteroatesynthetase (DHPS)-the key enzyme involved in folate synthesis), anti-impotent drugs, 23 and anti-glaucoma. [24][25] Sulfonamides act as protease inhibitors which are used to treat HIV infection (Amprenavir, 1), prevent and reduce the symptoms of altitude sickness (Acetazolamide, 2) and used to cure severe burns (Mafenide, 3).…”