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  • br Experimental br Acknowledgments br Human

    2022-05-20


    Experimental
    Acknowledgments
    Human immunodeficiency virus-1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), and without treatment results in a debilitating disease that cripples the immune system of the patient, increasing susceptibility to opportunistic diseases, ultimately leading to death. Since the approval of zidovudine (AZT) as the first HIV-1 inhibitor in 1987, significant advances have been made in the treatment of HIV- infection. The current preferred treatment, referred to as highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (cART), consists of combinations of two or more drugs that target specific viral processes. Since the advent of HAART, the quality of life and overall life span of the HIV-1 infected patients has significantly improved. Recent UNAIDS estimates indicate that approximately 36.7 million people are living with HIV-1 globally and that there were 1.8 million new infections and 1.0 million AIDS deaths in 2016, a significant decline when compared with the 3.4 million new infections (47%) estimated to have occurred in 2001 and 2.3 million AIDS deaths (56%) in 2005. HIV-1 therapy requires life-long adherence to a treatment regimen that if missed can lead to the rapid development of resistance to the one or more drugs used in the combination. The development of resistance consequently limits the number of treatment options available to an infected individual. Although current drug regimens are highly efficacious and generally well tolerated, there remain concerns about long-term toxicities. Development of cross-resistance within a mechanistic class and poor tolerability has necessitated a search for new drugs that are active against resistant viruses and safer for long-term use. Reverse transcriptase (RT), integrase (IN) and protease (PR) are three key DHEA involved in the HIV-1 life cycle. HIV-1 integrase irreversibly inserts the nascent reverse-transcribed, double stranded viral DNA into the host genome by a multistep biochemical process. There are two well-characterized catalytic steps involved in the integration process, the first of which is denoted as 3′-processing, in which the integrase enzyme cleaves a GT dinucleotide pair from each 3′-end of the viral cDNA long-terminal repeats, a process that occurs in the cytoplasm. The second catalytic step, referred to as strand transfer (ST), occurs in the nucleus, where integrase catalyzes the covalent insertion of reverse-transcribed, double-stranded viral DNA into the host chromosome. Inhibitors specifically targeting the inhibition of strand transfer reaction are designated as integrase strand transfer inhibitors (INSTIs). Previously, starting from the triketoacid lead (), optimization arrived at the amide ketoacid series , which displayed an improved antiviral activity in the cell culture HIV inhibition assay when compared with tri- or di-ketoacid derivatives. Further optimization studies focused on embedding the crucial structural elements of into heterocyclic ring systems, a survey that includes pyrrolidinedione carboxamides , the pyrimidinone carboxamides and pyridinone carboxamides . Raltegravir, the first integrase inhibitor approved for treating HIV/AIDS, belongs to the pyrimidinone class. In this article, we describe efforts to optimize the antiviral and pharmacokinetic properties of pyrimidinone carboxamides that led to the discovery of BMS-707035 (), a candidate that was advanced into clinical trials. Initial efforts were focused on the identification of an optimal substituent at the C2-position of the pyrimidinone core, and to this end a variety of C2-substituents were surveyed, including alkyl and cycloalkyl moieties, saturated heterocycles, acyclic and cyclic amines, and aryl and heteroaryl groups. The strand transfer and cell culture inhibition data for selected compounds which form the foundation for the discovery of BMS-707035 () are compiled in . Compounds – displayed good inhibitory activity in the strand transfer assay, which translated into potent antiviral activity in cell culture. However, there are subtle differences in the effects of the C2-substituents based on their structural attributes. The unsaturated cyclopentenyl- and 2,5-dihydrofuranyl-substituted analogs and are less potent than their corresponding saturated homologues and , respectively. In addition, the C2-carbocyclic carboxamides and exhibit reduced activity in the presence of human serum albumin (HSA), attributed to their lipophilic nature, leading to a lower free fraction. Not surprisingly, the more polar C2-heterocyclic compounds and exhibit a more moderate loss of activity in the presence of HSA. Remarkably, however, the C2-methylthiotetrahydrofuranyl carboxamide not only exhibited potent cellular inhibitory activity but also displayed a lower serum shift than the tetrahydrofuranyl analog , despite the fact that it is more lipophilic (cLogP = 0.98) than , (cLogP = 0.43).