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Development of HIV protease inhibitors: A survey

Chapter
Part of the Progress in Drug Research book series (PDR, volume 51)

Summary

In the treatment of infections caused by rapidly mutating viruses like human immunodeficiency virus (HIV), combination therapy with multiple drugs acting by different mechanisms offers several advantages over monotherapy. It may provide: synergistic effect, possible reduction of dosages and side-effects, and reduction of the chance of drug resistance. In the past few years, hundreds of HIV protease inhibitors have been synthesized and tested in order to overcome the limitations of reverse transcriptase inhibitors like zidovudine and others. In this review, emphasis is placed on the development of HIV protease inhibitors as antiviral agents against HIV, and structure-activity relationship analysis of saquinavir and related compounds. Limitations of some protease inhibitors and ways to overcome the shortcomings are presented. Among these many protease inhibitors four have been marketed during 1995–1997. They are saquinavir, ritonavir, indinavir and nelfinavir. Their different structural features, important physicochemical, pharmacokinetic and clinical profiles are presented in a table form for easy comparison. It is hoped that in the future new drugs based on additional mechanisms can be developed for the treatment of AIDS.

Keywords

AIDS antiviral agents chemotherapy HIV protease inhibitors indinavir nelfinavir ritonavir saquinavir structure-activity relationship 

Glossary of abbreviations

AHPBA

3-amino-2-hydroxy-4-phenylbutanoic acid

AHPPA

4-amino-3-hydroxy-5-phenylpentanoic acid

AIDS

acquired immunodeficiency syndrome

AZT

zidovudine

BN

β-naphthoyl

Boc

tert-butyloxycarbonyl

Clog P

calculated partition coefficient in octanol water

CNA

β-cyanoalanyl;

CYP3A4

cytochrome P450 3A4

C2

two-fold rotational symmetry

ddC

zalcitabine

ddI

didanosine

DIC

(4aS,8aS)-decahydro-3(S)-isoquinolinecarbonyl

HIV

human immunodeficiency virus

Log P

partition coefficient in octanol/water

MW

molecular weight

NRTI

nucleoside reverse transcriptase inhibitors

PIC

piperidine-2(S)-carbonyl

QC

quinoline2- carbonyl

RT

reverse transcriptase

SAR

structure-activity relationship

SMC

S-methyl-cysteinyl

3TC

lamivudine

tBu

tert-butyl

Z

benzyloxycarbonyl

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Copyright information

© Springer Basel AG 1998

Authors and Affiliations

  1. 1.Department of Pharmaceutical Sciences, School of PharmacyUniversity of Southern CaliforniaLos AngelesUSA

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