Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-12-04
2000-12-05
Davis, Zinna Northington
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544311, 544312, 544314, A61K 31505, C07D23946
Patent
active
061567590
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.
REFERENCES:
patent: 5112835 (1992-05-01), Miyasaka et al.
Ahgren, C., et al., 1995, Antimicrob. Agents Chemotherapy, 39, 1329-1335 The PETT Series, a New Class of Potent Nonnucleoside Inhibitors of Human Immunodeficiency Virus Type 1 Reverse Transcriptase.
Baba, M., et al., 1992, Antiviral Res, 17, 245-264 Highly potent and selective inhibition of HIV-1 replication by 6-phenylthiouracil derivatives.
Balzarini, J. et al., 1992, Proc. Natl. Acad. Sci. U S A, 89, 4392-4396 2',5'-Bis-O-(tert-butyldimethylsilyl)-3'-spiro-5"-(4"-amino-1",2"-oxathiol -2",2"-dioxide)pyrimidine (TSAO) nucleoside analogues: Hightly selective inhibitors of human immunodeficiency virus type 1 that are targeted at the viral reverse transcriptase.
Bartlett, P.A. et al., 1989, Molecular Recognition in Chemical and Biological Problems, Special Pub., Royal Chem. Soc., 78, 182-196 Caveat: A Program to Facilitate the Structure-derived Design of Biologically Active Molecules.
Bell, F. W., et al., 1995, J. Med. Chem., 38, 4929-4936 Penethylthiazolethiourea (PETT) Compounds, a New Class of HIV-1 Reverse Transcriptase Ihhibitors. 1. Syntheis and Basic Structure-Activity Relationship Studies of PETT Analogs.
Blaney, J.M. and Dixon, J.S., 1993, Perspectives in Drug Discovery and Design, 1, 301 A good ligand is hard to find: Automated docking methods.
Bohm, H. J., 1992, J. Comput. Aided. Mol. Des., 6, 593-606 LUDI: rule-based automatic design of new substituents for enzyme inhibitor leads.
Bohm, H.J., 1992, J. Comp. Aid. Molec. Design, 6, 61-78 The computer program LUDI: A new mehtod for the de novo design of enzyme inhibitors.
Bohm, H. J., J. Comput. Aided. Mol. Des., 1994, 8, 243-256; 1996 The development of a simple empirical scoring function to estimate the binding constant for a protein-ligand complex of konwn three-dimensional structure.
Bosworth, N., et al., 1989, Nature, 341: 167-168 Scintillation proximity assay.
Brooks, B.R. et al., 1983, J. Comp. Chem., 4, 187-217 CHARMM: A Program for Macromolecular Energy, Minimization, and Dynamics Calculations.
Burkert, U. and Allinger, N.L., 1982, Molecular Mechanics, ACS Monograph, 177, 59-78, American Chemical Society, D.C. Methods for the Computation of Molecular Geometry.
Cantrell, A. S., et al., 1996, J. Med. Chem., 39, 4261-4274 Phenethylthiazolythiourea (PETT) Compounds as a New Class of HIV-1 Reverse Transcriptase Inhibitors. 2. Synthesis and Further Structure-Activity Relationship Studies of PETT Analogs.
Connolly, M. L., 1983, Science, 221, 709-713 Solvent-Accessible Surfaces of Proteins and Nucleic Acids.
Danel, K. et al., 1997, Acta Chemica Scandinavica, 51, 426-430 Anti-HIV Active Napthyl Analogues of HEPT and DABO.
Danel, K. et al., 1998, J. Med. Chem., 41, 191-198 Synthesis and Anti-HIV-1 Activity of Novel 2,3-Dihydro-7H-thiazolo[3,2-.alpha.]pyrimidin-7-ones.
Danel, K., et al., 1996, J. Med. Chem., 39, 2427-2431 Synthesis and Potent Anti-HIV-1 Activity of Novel 6-Benzyluracil Analogues of 1-[2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine.
Das, K. et al., 1996, J. Mol. Biol., 264, 1085-1100 Crystal Structures of 8-Cl and 9-Cl TIBO Complexed with Wild-type HIV-1 RT and 8-Cl TIBO Complexed with the Tyr181Cys HIV-1 RT Drug-resistant Mutant.
De Clercq, E., 1992, J. Acquired Immune Defic. Syndr. Res. Human. Retrovirus, 8, 119-134.
Ding, J., 1995, et al., Nat. Struct. Biol., 2, 407-415 Structure of HIV-1 RT/TIBO R 86183 complex reveals similarity in the binding of diverse nonnucleoside inhibitors.
Erice, A. et al., 1993, Antimicrob. Ag. Chemother., 37, 835 Anti-Human Immunodeficiency Virus Type 1 Activity of an Anti-CD4 Immunoconjugate Containing Pokeweed Antiviral Protein.
Goodsell, D.S. and Olson, A.J., 1990, Proteins: Struct. Funct. Genet., 8, 195-202 The Molecular Biology of Human Immunodeficiency Virus Type 1 Infection.
Greene, W. C., 1991, New England Journal of Medicine, 324, 308-317 Automated Docking of Substrates to Proteins by Simulated Annealing.
Hopkins, A. L. et al., 1996, J. Med. Chem., 39, 1589-1600 Complexes of HIV-1 Reverse Transcriptase with Inhibitors of the HEPT Series Reveal Conformational Changes Relevant to the Design of Potent Non-Nucleoside Inhibitors.
Jones, T. A. et al., 1991, Acta Crystallogr. A., 47, 110-119 Improved Methods for Building Protein Models in Electron Denisty Maps and the Location of Errors in these Models.
Kohlstaedt, L. A. et al., 1992, Science, 256, 1783-1790 Crystal Structure at 3.5 .ANG. Resolution of HIV-1 Reverse Transcriptase Complexed with an Inhibitor.
Kuntz, I.D., et al., 1995, J. Mol. Biol., 1982, 161, 269-288 A Geometric Approach to Macromolecule--Ligand Interactions.
Luty, B. A. et al., 1995, J. Comp. Chem., 16, 454-464 A Molecular Mechanics/Grid Methods for Evaluation of Ligand--Receptor Interactions.
Mai, A. et al., 1997, J. Med. Chem., 40, 1447-1454 Dihydro(alkylthio)(naphthylmethyl)oxopyrimidines: Novel Non-Nucleoside Reverse Transcriptase Indhibitors of the S-DABO Series.
Marshall, G.R., 1987, Ann. Ref. Pharmacol. Toxicol., 27, 193 Computer-Aided Drug Design.
Martin, Y.C., 1992, J. Med. Chem., 35, 2145-2154 3D Database Searching in Drug Design.
Mitsuya, H. et al., 1990, Science, 249, 1533-1544 Molecular Targets for AIDS Therapy.
Nishibata, Y. and Itai, A., 1991, Tetrahedron, 47, 8985 Automatic Creation of Drug Candidate Structures Based on Receptor Structure. Startng Point for Artificial Lead Generation.
Pauwels, R. et al., 1990, Nature, 343, 470-474 Potent and selective inhibitionof HIV-1 replication in vitro by a novel series of TIBO derivatives.
Pontikis, R. et al., 1997, J. Med. Chem., 40, 1845-1854 Synthesis and Anti-HIV Activity of Novel N-1 Side Chain-Modified Analogs of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
Remington's Pharmaceutical Sciences, Chapter 43, 14th Ed., Mack Publishing Col, Easton PA 18042, USA Topical Drugs, 1970.
Ren, J. et al., 1995, Structure, 3, 915-926 The structure of HIV-1 reverse transcriptase complexed with 9-chloro-TIBO: lessons for inhibitor design.
Romero, D. L. et al., 1993, J. Med. Chem., 36, 1505-1508 Bis(heteroaryl)pipeazine (BHAP) Reverse Transcriptase Inhibitors: Structure-Activity Relationships of Novel Substituted Indole Analogues and the Identification of 1-[5-Methanesulfonamido-1H-indol-2-yl)-carbonyl]-4-[3-[(1-methylethyl)amin o]-pyridinyl]piperazine Monomethanseulfonate (U-90152S), a Second-Generation Clinical Candidate.
Tanaka, H. et al., 1991, J. Med. Chem., 34, 349-357 A New Class of HIV-1-Specific 6-Substituted Acyclouridine Derivatives: Synthesis and Anti-HIV-1 Activity of 5- or 6-Substituted Analogues of 1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT).
Tantillo, C. et al., 1994, J Mol Biol, 243, 369-387 Locations of Anti-AIDS Drug Binding Sites and Resistance Mutations in the Three-dimensional Structure of HIV-1 Reverse Transcriptase.
Uckun, F. M. et al., 1998, Antimicrobial Agents and Chemotherapy, 42, 383 TXU (Anti-CD7)-Pokeweed Antiviral Protein as a Potent Inhibitor of Human Immunodeficiency Virus.
Weiner, S.J. et al., 1984, J. Am. Chem. Soc., 106, 765-784 A New Force Field for Molecular Mechanical Simulation of Nucleic Acids and Proteins.
Zarling, J. M. et al., 1990, Nature, 347, 92-95 Inhibition of HIV replication by pokeweed antiviral protein targeted to CD4.sup.+ cells by monoclonal antibodies.
Tanaka, H. et al., "Synthesis of a potential photoaffinity labeling
Mao Chen
Uckun Fatih A.
Vig Rakesh
Davis Zinna Northington
Parker Hughes Institute
LandOfFree
Nonnucleoside inhibitors of reverse transcriptase, composite bin does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Nonnucleoside inhibitors of reverse transcriptase, composite bin, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Nonnucleoside inhibitors of reverse transcriptase, composite bin will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-962010