A Review on Pyridazinone Compounds ABT-963 as Selective Cyclooxygenase Inhibitor

Vicinally disubstituted pyridazinones act as potent and selective COX-2 inhibitors. Compound, ABT-963, (2-(3,4-difluoro-phenyl)-4-(3-hydroxy-3-methyl-butoxy)-5-(4-methanesulfonyl-phenyl)-2H-pyridazin-3-one) has an excellent selectivity (ratio of 276, COX-2/COX-1), improved aqueous solubility compared with celecoxib and rofecoxib, high oral anti-inflammatory potency and gastric safety in the animals. After oral administration, ABT-963 reduced prostaglandin (PG) E2 production and reduced the edema. ABT-963 dose dependently reduced nociception. ABT-963 significantly reduced bone loss and soft tissue destruction. ABT-963 is a highly selective COX-2 inhibitor that may be used in the treatment of the pain and inflammation associated with arthritis. whereas COX-2 is not normally expressed but is induced by cytokines, hormones, and growth factors [9,5]. Until recently, most clinically used inhibitors of PG formation inhibit both isozymes of COX. The result of inhibiting both isozymes of the enzyme is clinically significant inhibition of pain and inflammation accompanied by a significant incidence of GIT distress and renal complications. The GIT distress seen in the clinic can be modeled in rats or dogs by giving high doses of conventional NSAIDs. The studies have demonstrated that COX-2 expression is somewhat limited in that it is found in cells involved in the inflammatory process and in tissues that are undergoing accelerated proliferation such as those in cancer growth. The COX-1 is more widely expressed and is primarily involved in homeostasis [10]. Recent clinical and pharmacological studies demonstrate the benefit of selectively inhibiting COX-2 while leaving COX-1 active [7,11]. The search for selective COX-2 inhibitors has been a challenging one. The catalytic sites of the two enzymes are very similar [12] and thus it has been difficult to find selective compounds. Thus far, various agents have the tricyclic general structure first described for DuP-697 [13]. The marketed compounds share many of the structural characteristics of DuP-697. Therefore, a new distinct chemical series may offer the opportunity for improved selectivity in vitro, pharmacological superiority and enhanced safety. Structurally distinct chemical series of COX-2 inhibitors that have high selectivity and potency. These compounds, containing a central pyridazinone ring, in general show improved potency and selectivity compared with previously published compounds. The lead compound in the series, ABT-963 has improved selectivity in human whole blood, enhanced aqueous solubility compared with the currently marketed compounds, and high oral potency in vivo and gastric safety in animals [14]. The mechanism of action of anti-inflammatory and analgesic agents such Citation: Asif M (2016) A Review on Pyridazinone Compounds ABT-963 as Selective Cyclooxygenase Inhibitor. J Cell Sci Ther 7: 243. doi:10.4172/21577013.1000243.