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Synthesis 2001(15): 2203-2229
DOI: 10.1055/s-2001-18434
REVIEW
© Georg Thieme Verlag Stuttgart · New York

Syntheses of FDA Approved HIV Protease Inhibitors

Arun K. Ghosh*, Geoffrey Bilcer, Gary Schiltz
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, USA
Fax: +1(312)9960431; e-Mail: arunghos@uic.edu;
Further Information

Publication History

Received 17 August 2001
Publication Date:
05 August 2004 (online)

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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

Key words

HIV - protease - inhibitor - isostere - synthesis

16

A 3:1 mixture of azidodiol 22 and elimination product was produced where the elimination product was carried through to the deprotection stage before being separated.

77

For syntheses of ritonavir, see section 3.2.

80

The coupling was performed using a mixture of diastereomers of isostere 222. See Section 6.1 of this review for the preparation of isostere 222