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64 65

Heterocycle replacement in the HIV intergrase inhibitors also showed some interesting results (61). Systematically replacing the central ring of 66 with a series of aromatic systems having various substitution patterns provided a quick survey of biological activity in relation to the bisected angle of benzyl and diketo acid side chains. The intrinsic potency of these inhibitors increases as the angle of bisection increases from 60° to 118°. The angle of bisection was based on X-ray coordinates of similarly substituted heterocyclic/aromatic compounds.

67 68

Recently, celecoxib and refecoxib became the first cyclooxygenase-2 selective inhibitors to enter the market. A series of heteroaryl modified 1,2-diarylimidazoles were evaluated and shown to be potent and highly selective inhibitors of the human COX-2 (62). Bioisosteric replacement of the pyrazole of celecoxib with an imidazole and subsequent replacement of the phenyl group with various hetero aryl rings yielded inhibitors that exhibited desirable pharmacokinetic profiles. Additionally, excellent efficacy compounds in both acute and chronic models of Inflammation was observed for these compounds with no Gl toxicity in the rat up to 100mg/kg. Another series of COX-2 inhibitors with a central oxazole ring was also reported. The best compound in the series has an IC5o of 85nM against COX-2 and has a >1100-fold separation against COX-1. The leading compound also demonstrated good oral pharmacological activities in the rat carrageenan paw edema model and rat adjuvant arthritis model, without acute ulcerogenic toxicity in rats at doses up to 300mg/kg.

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