HIV Integrase Inhibitors - HIV integrase (IN) is the third constitutive viral enzyme required for replication, and therefore is an attractive target for chemotherapeutic intervention in the treatment of AIDS. A general lack of understanding of the molecular mechanisms of viral integration has hindered the discovery of small molecule integrase inhibitors with antiviral activity (45). Recently advances in integrase enzymology have pointed out the need to inhibit the strand transfer function of integrase to obtain significant antiviral activity (46). Accordingly, the most interesting integrase inhibitors from a drug discovery standpoint are those molecules that function as integrase strand transfer inhibitors (INSTI's). Important lead structures for medicinal chemistry efforts on INSTI drug development are a series of 1,3-dicarbonyl compounds typified by (1-(5-chloroindol-3-yl)-3-hydroxy-(2H-tetrazol-5-yl)propenone (5CITEP) (19) and the bioisosterically related 2,4-diketobutanoic acid 20. The 1,3-diketone 19 has an IC5o = 2.1 nM for strand transfer inhibition while the 2,4-diketobutanoic acid 20 is somewhat more potent (ICso = 0.01 nM) and shows good antiviral activity in cell culture (IC95 = 0.1 nM, iiib virus, MT4 cells) (47,48).
Improvements in potency and pharmacokinetics have been made to both prototype structures, which have resulted in clinical development candidates from both series. S-1360 (21) is a 1,3-diketopropane that combines features of both diaryldiketone 19 and diketoacid 20. S-1360 has a strand transfer inhibition IC50 = 20 nM and an antiviral EC90 = 720 nM (49). Human pharmacokinetics have been reported and suggest that to maintain adequate trough levels of drug, dosing may require 500 - 2,000 mg of S-1360 two or three times a day (50). The dicarbonyl portion of these molecules is believed to interact with the catalytically important Mg++ contained in the active site of integrase (51 ). Replacement of the pyruvic acid portion of 20 with an 8-hydroxy-1,6-naphthyridine led to a series of benzophenone like molecules that mimic the metal cation interaction of the diketobutanoic acid pharmacophore. The most potent example from this series of naphthyridine ketones is compound 22, which has an antiviral IC95 = 390 nM (52). Further elaboration of
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