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The development of HEPT-type HIV non-nucleoside reverse transcriptase inhibitors and its implications for DABO family.
- Source :
-
Current pharmaceutical design [Curr Pharm Des] 2012; Vol. 18 (27), pp. 4165-86. - Publication Year :
- 2012
-
Abstract
- 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) was discovered as the first HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) in 1989. The research on HEPT derivatives (HEPTs) has been lasted for more than 20 years and HEPT family is probably the most investigated NNRTI. Extensive molecular modifications on HEPT have led to many highly potent compounds with broad-resistance spectrum and optimal pharmacokinetic profiles. Moreover, X-crystallographic studies of HEPTs/RT complexes revealed the binding mode of HEPTs and the action mechanism of NNRTI, which has greatly facilitated the design of novel NNRTIs. Recently, the development of HEPTs was accelerated by the application of the "follow-on"-based chemical evolution strategies, such as designed multiple ligands (DMLs) and molecular hybridization (MH). Herein, this article will provide an insight into the development of HEPTs, including structural modifications, crystal structure of RT complexed with HEPTs and its structure-activity relationship (SAR). Additionally, this review also covers the emerging HEPT related dual inhibitors and HEPT-pyridinone hybrids, as well as the contributions of HEPTs to the development of dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family, thus highlighting the importance of HEPTs on the development of NNRTIs.
- Subjects :
- Anti-HIV Agents chemistry
Crystallography, X-Ray
Drug Design
HIV Infections drug therapy
HIV Infections enzymology
HIV-1 drug effects
HIV-1 enzymology
Humans
Pyrimidines chemistry
Pyrimidines pharmacology
Reverse Transcriptase Inhibitors chemistry
Structure-Activity Relationship
Thymine analogs & derivatives
Thymine pharmacology
Anti-HIV Agents pharmacology
HIV Reverse Transcriptase antagonists & inhibitors
Reverse Transcriptase Inhibitors pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-4286
- Volume :
- 18
- Issue :
- 27
- Database :
- MEDLINE
- Journal :
- Current pharmaceutical design
- Publication Type :
- Academic Journal
- Accession number :
- 22621244
- Full Text :
- https://doi.org/10.2174/138161212802430440