Heterocyclic nonnucleoside inhibitors of reverse transcriptase

Details Heterocyclic nonnucleoside inhibitors of reverse transcriptase Heterocyclic nonnucleoside inhibitors of reverse transcriptase

1998-12-04

2001-01-30

Davis, Zinna Northington (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S305000

Reexamination Certificate

active

06180654

ABSTRACT:

Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
The inventors acknowledge and appreciate the assistance of Dr. Elise Sudbeck.
BACKGROUND OF THE INVENTION
Design of potent inhibitors of human immunodeficiency virus (HIV-1) reverse transcriptase (RT), an enzyme responsible for the reverse transcription of the retroviral RNA to proviral DNA, has been a focal point in translational AIDS research efforts (Greene, W. C.,
New England Journal of Medicine,
1991, 324, 308-317; Mitsuya, H. et al.,
Science,
1990, 249, 1533-1544; De Clercq, E.,
J. Acquired Immune Defic. Syndr. Res. Human. Retrovirus,
1992, 8, 119-134). Promising inhibitors include nonnucleoside inhibitors (NNI), which bind to a specific allosteric site of HIV-1 RT near the polymerase site and interfere with reverse transcription by altering either the conformation or mobility of RT, thereby leading to noncompetitive inhibition of the enzyme (Kohlstaedt, L. A. et al.,
Science,
1992, 256, 1783-1790).
NNI of HIV-1 RT include the following:
(a) 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymines (HEPT; Tanaka, H. et al.,
J. Med. Chem.,
1991, 34, 349-357; Pontikis, R. et al.,
J. Med. Chem.,
1997, 40, 1845-1854; Danel, K., et al.,
J. Med. Chem.,
1996, 39, 2427-2431; Baba, M., et al.,
Antiviral Res,
1992, 17, 245-264);
(b) tetrahydroimidazobenzodiazepinethiones (TIBO; Pauwels, R. et al.,
Nature,
1990, 343, 470-474);
(c) bis(heteroaryl)piperazines (BHAP; Romero, D. L. et al.,
J. Med Chem.,
1993, 36, 1505-1508);
(d) dihydroalkoxybenzyloxopyrimidine (DABO; Danel, K. et al.,
Acta Chemica Scandinavica,
1997, 51, 426-430; Mai, A. et al.,
J. Med. Chem.,
1997, 40, 1447-1454);
(e) 2′-5′-bis-O-(tertbutyldimethylsilyl)-3′-spiro-5″-(4″-amino-1″, 2″-oxathiole-2″, 2″-dioxide)pyrimidines (TSAO; Balzarini, J. et al.,
Proc. Natl. Acad. Sci. USA,
1992, 89, 4392-4396); and
(f) phenethylthiazolylthiourea (PETT) derivatives (Bell, F. W. et al.,
J. Med. Chem.,
1995, 38, 4929-4936; Cantrell, A. S. et al.,
J. Med. Chem.,
1996, 39, 4261-4274).
Current protein structure-based drug design efforts rely heavily on crystal structure information of the target binding site. A number of crystal structures of RT complexed with NNIs (including &agr;-APA, TIBO, Nevirapine, BHAP and HEPT derivatives) have been reported, and such structural information provides the basis for further derivatization of NNI aimed at maximizing binding affinity to RT. However, the number of available crystal structures of RT NNI complexes is limited, and no structural information has been reported for RT-PETT complexes or RT-DABO complexes. Given the lack of structural information, researchers must rely on other design procedures for preparing active PETT and DABO derivatives. One of the first reported strategies for systematic synthesis of PETT derivatives was the analysis of structure-activity relationships independent of the structural properties of RT and led to the development of some PETT derivatives with significant anti-HIV activity (Bell, F. W. et al.,
J. Med. Chem.,
1995, 38, 4929-4936; Cantrell, A. S. et al.,
J. Med. Chem.,
1996, 39, 4261-4274). The inclusion of structural information in the drug design process should lead to more efficient identification of promising RT inhibitors.
Although the crystal structure of an RT-NNI complex can be used to provide useful information for the design of a different type of NNI, its application is limited. For example, an analysis of the RT-APA (&agr;-anilinophenylacetamide) complex structure would not predict that the chemically dissimilar inhibitor TNK (6-benzyl-1-benzyloxymethyl uracil) could bind in the same region. The RT-APA structure reveals that there would not be enough room in the APA binding site for the 1-benzyloxymethyl group of TNK (Hopkins, A. L. et al.,
J. Med. Chem.,
1996
,
39
,
1589
-
1600
). Nevertheless TNK is known to bind in this region as evidenced by the crystal structure of RT-TNK which shows that RT residues can adjust to accommodate the 1-benzyloxymethyl group. Conversely, an analysis of the RT-TNK complex would not predict favorable binding of APA in the TNK binding site. The structure does not show how residue E138 can move to accommodate the 2-acetyl group of the &agr;-APA inhibitor.
Thus, any NNI binding pocket model based on an individual RT-NNI crystal structure would have limited potential for predicting the binding of new, chemically distinct inhibitors. To overcome this problem, the invention disclosed herein uses the NNI binding site coordinates of multiple, varied RT-NNI structures to generate a composite molecular surface. A specific embodiment of the invention is a composite molecular surface or binding pocket generated from nine distinct RT-NNI complexes, and reveals a larger than presumed NNI binding pocket not shown or predicted by any of the individual structures alone (FIG.
2
A). This novel composite binding pocket, together with a computer docking procedure and a structure-based semi-empirical score function, provides a guide to predict the energetically favorable position of novel PETT, DABO, and HEPT derivatives, as well as other novel compounds, in the NNI binding site of RT.
The invention further provides a number of computational tools which set forth a cogent explanation for the previously unexplained and not understood relative activity differences among NNIs, including PETT, DABO, and HEPT derivatives, and reveals several potential ligand derivatization sites for generating new active derivatives. Disclosed herein is the structure-based design of novel HEPT derivatives and the design and testing of non-cytotoxic PETT and DABO derivatives which abrogate HIV replication in human peripheral blood mononuclear cells at nanomolar concentrations with an unprecedented selectivity index of >10
5
.
One procedure useful in structure-based rational drug design is docking (reviewed in Blaney, J. M. and Dixon, J. S.,
Perspectives in Drug Discovery and Design,
1993, 1, 301). Docking provides a means for using computational tools and available structural data on macromolecules to obtain new information about binding sites and molecular interactions. Docking is the placement of a putative ligand in an appropriate configuration for interacting with a receptor. Docking can be accomplished by geometric matching of a ligand and its receptor, or by minimizing the energy of interaction. Geometric matching is faster and can be based on descriptors or on fragments.
Structure-based drug design efforts often encounter difficulties in obtaining the crystal structure of the target and predicting the binding modes for new compounds. The difficulties in translating the structural information gained from X-ray crystallography into a useful guide for drug synthesis calls for continued effort in the development of computational tools. While qualitative assessments of RT-inhibitor complexes provide helpful information, systematic quantitative prediction of inhibitory activity of new compounds based on structural information remains a challenge.
There is a need for more complete information on the structure and flexibility of the NNI binding pocket and for an improved model of the binding pocket to serve as a basis for rational drug design. In addition, there is a need for more effective inhibitors of reverse transcriptase, particularly HIV-1 reverse transcriptase.
The invention disclosed herein addresses these needs by providing a model for the three-dimensional structure of the RT-NNI binding pocket based on the available backbone structure of RT-DNA complex and full structure of RT complexed with several NNI compounds. Structural information from multiple RT-NNI complexes was combined to provide a suitable working model. In one embodiment, the NNI binding site coordinates of nine RT-NNI structur

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