Syntheses of FDA Approved HIV Protease Inhibitors

Abstract The treatment of HIV and AIDS was revolutionized by the introduction of peptidomimetic aspartyl protease inhibitors. One of the major limitations of this type of therapy is that higher therapeutic doses are necessary because of the presence of ‘peptide-like’ features in the drugs. Therefore, adequate supplies and cost effective syntheses of these drugs are of utmost importance. To date, there are six protease inhibitors approved by the United States Food and Drug Administration (FDA) for the treatment of HIV and AIDS. This review focuses on the published syntheses of currently FDA approved HIV protease inhibitor drugs, their isosteres and ligands. 1 Introduction 2 Saquinavir (Invirase ® , Fortovase ® , Ro 31-8959) 2.1 Synthesis of the Saquinavir Isostere 2.2 Synthesis of the Decahydroisoquinoline Fragment of Saquinavir 2.3 Synthesis of Saquinavir 3 Nelfinavir (Viracept ® , AG1343) 3.1 Synthesis of the Nelfinavir Isostere 3.2 Synthesis of Nelfinavir 4 Amprenavir (Agenerase ® , VX-478, 141W94) 4.1 Synthesis of the Amprenavir Isostere 4.2 Synthesis of Amprenavir 5 Indinavir (Crixivan ® , L-735,524, MK-639) 5.1 Synthesis of the Indinavir 2-Piperazine Fragment 5.2 Synthesis of the Indinavir Isostere 5.3 Synthesis of Indinavir 6 Ritonavir (Norvir ® , ABT-538) 6.1 Synthesis of the Ritonavir Isostere 6.2 Synthesis of Ritonavir 7 Lopinavir (Aluviran ® , ABT-378, Component of Kaletra ® ) 7.1 Synthesis of the Lopinavir Cyclic Urea Fragment 7.2 Synthesis of Lopinavir 8 Conclusion