Derivatives of pyridinones were found to inhibit human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevent the spread of HIV-1 infection in cell culture without an appreciable effect on other retroviral or cellular polymerases. 3-{[(4,7-Dimethyl-1,3-benzoxazol-2-yl)methyljamino}-5-ethyl-6methylpyridin-2(LH)-one (L-697,639) and 3-{[(4,7-dichloro-1,3-benzoxazol-2-yl)methylJamino}-5-ethyl--methylpyridin-2(IH)-one (L-697,661) Infection with the human immunodeficiency virus type 1 (HIV-1) causes progressive destruction of the immune system, which ultimately results in AIDS. An essential step in the life cycle of HIV-1 is reverse transcription of the viral RNA genome to produce a double-stranded DNA copy. This process is mediated by the virally encoded reverse transcriptase (RT). Thus, RT is a potential therapeutic target and, indeed, nucleoside analog inhibitors of RT, such as 3'-azido-3'-deoxythymidine (AZT) and dideoxyinosine (ddI), are clinically effective drugs for treating HIV-1 infection (1, 2). However, their effectiveness is limited by toxicities, which may reflect inhibition of cellular polymerases and/or alteration of nucleoside pools, given that the nucleoside analogs are phosphorylated (in competition with natural nucleosides) to their active form by cellular kinases (3, 4). The emergence of AZT-resistant virus (5) further emphasizes the need to develop selective RT inhibitors that can be used either alone or in combination with nucleoside analogs. The development of specific RT inhibitors is the subject ofthis communication. (L-697,661) were synthesized by alkylation of 3-amino-5-ethyl-6-methylpyridin-2(1H)-one with either N-hydroxymethylphthalimide or the appropriate 2-halomethylbenzoxazole. Requisite aminopyridinone was obtained from condensation of 3-formyl-2-pentanone with nitroacetamide followed by catalytic reduction.Synthesis of ethylene derivative 5-ethyl-6-methyl-3-(2-phthalimidoethyl)pyridin-2(1H)-one (L-693,593) began with the condensation of 3-formyl-2-pentanone and cyanoacetamide to give 3-cyano-5-ethyl-6-methylpyridin-2(1H)-one. Reaction of this cyanopyridinone with POCl3 followed by methanolysis and reduction with diisobutylaluminum hydride led to 5-ethyl-2-methoxy-6-methylpyridine-3-carboxaldehyde. The aldehyde function was treated with trimethylsilyl cyanide, and the resulting cyanohydrin was reduced with lithium aluminum hydride to the amino alcohol. After conversion of the amino group to phthalimide, demethylation ofthe 2-methoxy group and alcohol dehydration was accomplished in one step by heating with pyridine hydrochloride. Catalytic reduction of the olefin formed yielded ethylene analog L-693,593. The structures of all pyridinones synthesized are consistent with their NMR spectra, and all compounds gave an acceptable combustion analysis (within 0.4%).H1V-1 RT Assays. rC-dG.

Human immunodeficiency virus type 1 (HIV-1)-specific pyridinone reverse transcriptase (RT) inhibitors prevent HIV-1 replication in cell culture (M.

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The PI3K-Akt pathway is dysregulated in the majority of solid tumors. Pharmacological inhibition of Akt is a promising strategy for treating tumors resistant to growth factor receptor antagonists due to mutations in PI3K or PTEN. We have developed allosteric, isozyme-specific inhibitors of Akt activity and activation, as well as ex vivo kinase assays to measure inhibition of individual Akt isozymes in tissues. Here we describe the relationship between PK, Akt inhibition, hyperglycemia and tumor efficacy for a selective inhibitor of Akt1 and Akt2 (AKTi). In nude mice, AKTi treatment caused transient insulin resistance and reversible, dose-dependent hyperglycemia and hyperinsulinemia. Akt1 and Akt2 phosphorylation was inhibited in mouse lung with EC50 values of 1.6 and 7 μM, respectively, and with similar potency in other tissues and xenograft tumors. Weekly subcutaneous dosing of AKTi resulted in dose-dependent inhibition of LNCaP prostate cancer xenografts, an AR-dependent tumor with PTEN deletion and constitutively activated Akt. Complete tumor growth inhibition was achieved at 200 mpk, a dose that maintained inhibition of Akt1 and Akt2 of greater than 80% and 50%, respectively, for at least 12 hours in xenograft tumor and mouse lung. Hyperglycemia could be controlled by reducing Cmax, while maintaining efficacy in the LNCaP model, but not by insulin administration. AKTi treatment was well tolerated, without weight loss or gross toxicities. These studies supported the rationale for clinical development of allosteric Akt inhibitors and provide the basis for further refining of pharmacokinetic properties and dosing regimens of this class of inhibitors.