Synthesis, Structure−Activity Relationships, and in Vivo Evaluations of Substituted Di-tert-butylphenols as a Novel Class of Potent, Selective, and Orally Active Cyclooxygenase-2 Inhibitors. 2. 1,3,4- and 1,2,4-Thiadiazole Series

Abstract

Two isoforms of the cyclooxygenase (COX) enzyme have been identified: COX-1, which is expressed constitutively, and COX-2, which is induced in inflammation. Recently, it has been shown that selective COX-2 inhibitors have antiinflammatory activity and lack the GI side effects typically associated with NSAIDs. Initial mass screening and subsequent SAR studies have identified 6b (PD164387) as a potent, selective, and orally active COX-2 inhibitor. It had IC50 values of 0.14 and 100 microM against recombinant human COX-2 and purified ovine COX-1, respectively. It inhibited COX-2 activity in the J774A.1 cell line with an IC50 of 0.18 microM and inhibited COX-1 activity in platelets with an IC50 of 3.1 microM. The choline salt of compound 6b was also orally active in vivo with an ED40 of 7. 1 mg/kg in the carrageenan footpad edema (CFE) assay. In vivo studies in rats at a dose of 100 mg/kg showed that this compound inhibited gastric prostaglandin E2 (PGE2) production in gastric mucosa by 77% but caused minimal GI damage. SAR studies of this chemical series revealed that the potency and selectivity are very sensitive to minor structural changes.

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs

“…HTS has provided rapid lead identification for numerous drug targets (1)(2)(3)(4)(5)(6)(7)(8); however, HTS also has major drawbacks, including a significant level of false positives and false negatives and low hit rates for many targets (9). Successful leads from HTS can also suffer from poor bioavailability and unwanted toxicity profiles of compounds.…”

Synthesis and antituberculosis activity of 2-(aryl/alkylamino)-5-(4-aminophenyl)-1,3,4-thiadiazoles and their Schiff bases

“…Furthermore, thiadiazoles possess antifungal, 6 antituberculosis, [7][8][9] anticancer, 10,11 antimicrobial, [12][13][14][15] anti-inflammatory, [16][17][18] antihypertensive, 19,20 local anesthetic, 21 anticonvulsant, [22][23][24] and antitrypanosomal 25 activities.…”

Studies on some biologically active substituted 4(3H)-quinazolinones. Part 1. Synthesis, characterization and anti-inflammatory-antimicrobial activity of 6,8-disubstituted 2-phenyl-3-[substituted-benzothiazol-2-yl]-4(3H)-quinazolinones

“…3,4 This is because of decreased levels of PG's which has dual functions; mediation of inflammation and cytoprotection in the stomach and intestine 5 . Recent reports suggest that cyclo-oxygenase enzyme exist in two isoforms COX-1 and COX-2, which are regulated differently 6 . COX-1 is responsible for the synthesis of gastroprotective PG's in the GI and proaggregatory thromboxane in blood platelets, 7 whereas short lived COX-2 is induced by pro-inflammatory stimuli such as endotoxin, bacterial lipopolysaccharide, growth factors, cytokines, mitogens, and tumor-promoting agents.…”

“…12 Hence a potent and selective COX-2 should block the production of prostaglandin in inflammatory cells without affecting in the homeostatic and gastro-protective actions mediated by COX-1. 6 The search continues to develop new drugs that have potent anti-inflammatory activity with minimum side effects. Although many NSAID's are in the market, the present therapeutic approach and chemical design of NSAID's are now targeted towards the development of selective COX-2 inhibitors and as a result, several selective COX-2 inhibitors are commercially available.…”