4,5-Dihydroxypyrimidine Carboxamides and N-Alkyl-5-hydroxypyrimidinone Carboxamides Are Potent, Selective HIV Integrase Inhibitors with Good Pharmacokinetic Profiles in Preclinical Species
文摘
The dihydroxypyrimidine carboxamide 4a was discoveredas a potent and selective HIV integrase strand transfer inhibitor. Theoptimization of physicochemical properties, pharmacokinetic profiles,and potency led to the identification of 13 in the dihydroxypyrimidineseries and 18 in the N-methylpyrimidinone series having low nanomolaractivity in the cellular HIV spread assay in the presence of 50% normalhuman serum and very good pharmacokinetics in preclinical species.