The development of cyclic sulfolanes as novel and high-affinity P2 ligands for HIV-1 protease inhibitors
| Autor: | A K, Ghosh, H Y, Lee, W J, Thompson, C, Culberson, M K, Holloway, S P, McKee, P M, Munson, T T, Duong, A M, Smith, P L, Darke |
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| Rok vydání: | 1994 |
| Předmět: |
Models
Molecular Stereochemistry medicine.medical_treatment Molecular Conformation Cyclopentanes Thiophenes Antiviral Agents chemistry.chemical_compound Structure-Activity Relationship HIV-1 protease HIV Protease Piperidines Drug Discovery medicine Asparagine Binding site Saquinavir chemistry.chemical_classification Protease Binding Sites biology Molecular Structure Chemistry Ligand Quinoline HIV Protease Inhibitors Isoquinolines Enzyme Enzyme inhibitor Cyclization biology.protein HIV-1 Quinolines Molecular Medicine |
| Zdroj: | Journal of medicinal chemistry. 37(8) |
| ISSN: | 0022-2623 |
| Popis: | Design and synthesis of a novel series of protease inhibitors incorporating conformationally constrained cyclic ligands for the &-substrate binding site of HIV-1 protease is described. We recently reported urethanes of 3-tetrahydrofuranyl as PZ ligands for HIV-1 protease inhibitors. Subsequently, we have found that the urethane of 3(S)-hydroxysulfolane further increased the in uitro potency of these inhibitors. Furthermore, introduction of a small 2-alkyl group cis to the 3-hydroxyl group of either heterocyclic system further enhanced enzyme affinity. The cis-2isopropyl group thus far offered optimum enhancement of the inhibitory properties. This led to the discovery of inhibitor 43 (ICm 3.5 nM, CICSS 50 f 14 nM) of comparable in uitro antiviral potency to the current clinical candidate 1 (Ro 31-8959) but of reduced molecular weight due to the exclusion of the P3 quinoline ligand. Also, it has been demonstrated that the octahydropyrindene derivative 34 is an effective replacement of the Pi decahydroisoquinoline derivative. The development of an effective therapeutic agent for the treatment of AIDS continues to be a challenging problem in medicinal research. Since the discovery that a virally encoded HIV protease is vital for propagation, inhibition of this enzyme became a major therapeutic target for AIDS chemotherapy.’ Consequently, numerous efforts aimed at developing potent and selective inhibitors of HIV protease have appeared in the literature.2 During the course of our research, we have designed and synthesized a number of conformationally constrained cyclic ligands for the HIV protease substrate binding site.= We recently reported that the incorporation of an unnatural amino acid such as (2$,3’R)-tetrahydrofuranylglycine in place of asparagine at the PZ subsite of the present clinical candidate 1 (Ro 31-8959)eled to inhibitor 2 with enhanced enzyme affinity as well as antiviral p~tency.~ Subsequently, we have found that the removal of the P3 quinoline ligand and incorporation of a urethane of (3S)-tetrahydrofuran as the PZ ligand resulted in inhibitor 3 with an ICs0 value of 132 nM.5 The urethanes of 3(S)-hydroxysulfolane provided further potency enhancement relative to the heterocycle (3s)-tetrahydrofuran. Furthermore |
| Databáze: | OpenAIRE |
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