Nonnucleoside inhibitors of reverse transcriptase, composite binding pocket and methods for use thereof

• US 20050153995A1
• Filed: 10/12/2004
• Published: 07/14/2005
• Est. Priority Date: 03/17/1998
• Status: Abandoned Application

• Current Assignee: Parker Hughes Institute
• Original Assignee: Parker Hughes Institute
• Inventors: Uckun, Fatih A., Mao, Chen, Vig, Rakesh
• Application Number:
  US10/964,976
• Publication Number:
  US 20050153995A1
• Time in Patent Office: Days
• US Class Current: 514/269
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 239/47 One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Abstract

Novel compounds that are potent inhibitors of HIV reverse transcriptase (RT) are described in the invention. Thes novel compounds also inhibit replication of a retrovirus, such as human immunodeficiency virus-1 (HIV-1). The novel compounds of the invention include analogs and derivatives of phenethylthiazolylthiourea (PETT), of dihydroalkoxybenzyloxopyrimidine (DABO), and of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT). The invention additionally provides a composite HIV reverse-transcriptase (RT) nonnucleoside inhibitor (NNI) binding pocket constructed from a composite of multiple NNI-RT complexes The composite RT-NNI binding pocket provides a unique and useful tool for designing and identifying novel, potent inhibitors of reverse transcriptase.

Claims

1-24. -24. (canceled)

25. A compound comprising the formula:

26. The compound of claim 25, wherein R₁ is alkyl, alkenyl, ROH, or RNH₂.

27. The compound of claim 25, wherein R₁ is methyl, ethyl, or isopropyl.

28. The compound of claim 25, wherein R₂ is halo, alkyl, or C1-C3 alkoxy.

29. The compound of claim 25, wherein X is S.

30. The compound of claim 25, wherein X and Y are each S.

31. The compound of claim 25, wherein R₃ is C1-C3 alkyl.

63. A method for treating a subject infected with a retrovirus, the method comprising administering to the subject an effective antiviral dose of any one of the compounds of claim 25.

64. A method for killing HIV virus in a cell, the method comprising administering to the cell an effective anti-viral amount of any one of the compounds of claim 25.

65. A method for inhibiting the growth of HIV in a cell, the method comprising administering to the cell an effective inhibitory dose of any of the compounds of claim 25.

32-62. -62. (canceled)

66-130. -130. (canceled)