RESUMEN
Human immunodeficiency virus (HIV) protease inhibitors (PIs) are important components of many highly active antiretroviral therapy regimens. However, development of phenotypic and/or genotypic resistance can occur, including cross-resistance to other PIs. Development of resistance takes place because trough levels of free drug are inadequate to suppress preexisting resistant mutant variants and/or to inhibit de novo-generated resistant mutant variants. There is thus a need for new PIs, which are more potent against mutant variants of HIV and show higher levels of free drug at the trough. We have optimized a series of substituted sulfonamides and evaluated the inhibitors against laboratory strains and clinical isolates of HIV type 1 (HIV-1), including viruses with mutations in the protease gene. In addition, serum protein binding was determined to estimate total drug requirements for 90% suppression of virus replication (plasma IC(90)). Two compounds resulting from our studies, designated DPC 681 and DPC 684, are potent and selective inhibitors of HIV protease with IC(90)s for wild-type HIV-1 of 4 to 40 nM. DPC 681 and DPC 684 showed no loss in potency toward recombinant mutant HIVs with the D30N mutation and a fivefold or smaller loss in potency toward mutant variants with three to five amino acid substitutions. A panel of chimeric viruses constructed from clinical samples from patients who failed PI-containing regimens and containing 5 to 11 mutations, including positions 10, 32, 46, 47, 50, 54, 63, 71, 82, 84, and 90 had mean IC(50) values of <20 nM for DPC 681 and DPC 681, respectively. In contrast, marketed PIs had mean IC(50) values ranging from 200 nM (amprenavir) to >900 nM (nelfinavir).
Asunto(s)
Infecciones por VIH/virología , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Sulfonamidas/farmacología , Administración Oral , Animales , Proteínas Sanguíneas/metabolismo , Perros , Farmacorresistencia Microbiana , Femenino , Genotipo , Inhibidores de la Proteasa del VIH/farmacocinética , Humanos , Inyecciones Intravenosas , Masculino , Unión Proteica , Sulfonamidas/farmacocinéticaRESUMEN
A series of 4,4-disubstituted quinolinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The C-3 substituted compound 9h displayed improved antiviral activity against clinically significant single (K103N) and double (K103N/L100I) mutant viruses.
Asunto(s)
Antivirales/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Quinolonas/farmacología , Antivirales/síntesis química , Resistencia a Medicamentos/genética , VIH-1/genética , Humanos , Concentración 50 Inhibidora , Mutación/genética , Quinolonas/síntesis químicaRESUMEN
A series of 4,1-benzoxazepinone analogues of efavirenz (Sustiva) as potent NNRTIs has been discovered. The cis-3-alkylbenzoxazepinones are more potent then the trans isomers and can be synthesized preferentially by a novel stereoselective cyclization. The best compounds are potent orally bioavailable inhibitors of both wild-type HIV-1 and its clinically relevant K103N mutant virus, but are highly protein-bound in human plasma.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Oxazinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Alquinos , Animales , Benzoxazinas , Ciclopropanos , Transcriptasa Inversa del VIH/genética , Humanos , Macaca mulatta , Oxazinas/química , Oxazinas/farmacocinética , Unión Proteica , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacología , Quinazolinonas , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacocinética , Relación Estructura-ActividadRESUMEN
The cyclic urea inhibitors of HIV-1 protease generally have two hydroxyl groups on the seven-membered ring. In this study, free energy perturbation and continuum electrostatic calculations were used to study the contributions of the two hydroxyl groups to the binding affinity and solubility of a cyclic urea inhibitor DMP323. The results indicated that the inhibitor with one hydroxyl group has better binding affinity and solubility than the inhibitor with two hydroxyl groups. Therefore, removal of one hydroxyl group from DMP323 may help to improve the properties of DMP323. This is also likely to be true for other cyclic urea inhibitors. The study also illustrated the difficulty in accurate modeling of the binding affinities of HIV-1 protease inhibitors, which involves many possible protonation states of the two catalytic aspartic acids in the active site of the enzyme.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/metabolismo , Urea/análogos & derivados , Azepinas , Sitios de Unión , Inhibidores de la Proteasa del VIH/farmacología , Técnicas In Vitro , Modelos Moleculares , Electricidad Estática , Termodinámica , Urea/química , Urea/metabolismo , Urea/farmacologíaRESUMEN
Studies on the biotransformation of the clinically important non-nucleoside reverse transcriptase inhibitor efavirenz have shown that oxidation and secondary conjugation are important components of the processing of this molecule in vivo. We have synthesized metabolites of efavirenz to confirm their structure and to evaluate their activity as antivirals.
Asunto(s)
Antivirales/síntesis química , Antivirales/farmacología , Oxazinas/metabolismo , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Alquinos , Animales , Antivirales/química , Benzoxazinas , Biotransformación , Ciclopropanos , Humanos , Estructura Molecular , Oxazinas/farmacología , Inhibidores de la Transcriptasa Inversa/químicaRESUMEN
A series of unique 3,3a-dihydropyrano[4,3,2-de]quinazolin-2(1H)-ones and a 2a,5-dihydro-2H-thieno[4,3,2-de]quinazo-line-4(3H)-thione were found to be HIV-1 non-nucleoside reverse transcriptase inhibitors. One of these compounds, as the racemate, possessed an IC90 = 4.6 nM against wild-type virus in a whole cell antiviral assay and had an IC90 = 76 and 897 nM against the clinically significant K103N and K103N/L100I mutant viruses, respectively.
Asunto(s)
Transcriptasa Inversa del VIH/antagonistas & inhibidores , Piranos/farmacología , Quinazolinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Sitios de Unión , Técnicas Químicas Combinatorias , Resistencia a Medicamentos , Transcriptasa Inversa del VIH/genética , Compuestos Heterocíclicos con 2 Anillos/síntesis química , Compuestos Heterocíclicos con 2 Anillos/farmacología , Compuestos Heterocíclicos con 3 Anillos/síntesis química , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Mutación Puntual , Piranos/síntesis química , Quinazolinas/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
3-Alkoxymethyl- and 3-aryloxymethyl-2-pyridinones were synthesized and evaluated for activity as non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV-1. It was found that several compounds were potent inhibitors of HIV-1 with the most potent compound 24 exhibiting an IC90 = 32 nM. Compound 24 also possessed a potent resistance profile as demonstrated by submicromolar IC90s against several clinically meaningful mutant virus strains.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , Piridonas/farmacología , Fármacos Anti-VIH/farmacología , Técnicas Químicas Combinatorias , Efecto Citopatogénico Viral/efectos de los fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Flúor/química , Transcriptasa Inversa del VIH/genética , VIH-1/efectos de los fármacos , VIH-1/genética , Concentración 50 Inhibidora , Mutación , Piridonas/síntesis química , Relación Estructura-ActividadRESUMEN
BACKGROUND: Silicon is the element most similar to carbon, and bioactive organosilanes have therefore been of longstanding interest. Design of bioactive organosilanes has often involved a systematic replacement of a bioactive molecule's stable carbon atoms with silicon. Silanediols, which are best known as unstable precursors of the robust and ubiquitous silicone polymers, have the potential to mimic an unstable carbon, the hydrated carbonyl. As a bioisostere of the tetrahedral intermediate of amide hydrolysis, a silanediol could act as a transition state analog inhibitor of protease enzymes. RESULTS: Silanediol analogs of a carbinol-based inhibitor of the HIV protease were prepared as single enantiomers, with up to six stereogenic centers. As inhibitors of this aspartic protease, the silanediols were nearly equivalent to both their carbinol analogs and indinavir, a current treatment for AIDS, with low nanomolar K(i) values. IC(90) data from a cell culture assay mirrored the K(i) data, demonstrating that the silanediols can also cross cell membranes and deliver their antiviral effects. CONCLUSIONS: In their first evaluation as inhibitors of an aspartic protease, silanediol peptidomimetics have been found to be nearly as potent as currently available pharmaceutical agents, in enzyme and cell protection assays. These neutral, cell-permeable transition state analogs therefore provide a novel foundation for the design of therapeutic agents.
Asunto(s)
Diseño de Fármacos , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/efectos de los fármacos , Compuestos de Organosilicio/química , Compuestos de Organosilicio/farmacología , Células Cultivadas , Humanos , Modelos MolecularesRESUMEN
A series of 3,3-disubstituted quinoxalinones was prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The N-allyl (6b and 6f), N-cyclopropylmethyl (6a, 6g, 6h, and 6k) and N-carboalkoxy (6m-6y) substituted compounds displayed activity comparable or better than Efavirenz and GW420867X.
Asunto(s)
Transcriptasa Inversa del VIH/efectos de los fármacos , Quinoxalinas/síntesis química , Quinoxalinas/farmacología , Inhibidores de la Transcriptasa Inversa/síntesis química , Inhibidores de la Transcriptasa Inversa/farmacología , Evaluación de MedicamentosRESUMEN
A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , Mutación , Quinazolinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Alquinos , Fármacos Anti-VIH/sangre , Fármacos Anti-VIH/farmacología , Benzoxazinas , Proteínas Sanguíneas/metabolismo , Ciclopropanos , VIH-1/genética , Humanos , Estructura Molecular , Oxazinas/sangre , Oxazinas/farmacología , Unión Proteica , Quinazolinas/sangre , Quinazolinas/farmacología , Inhibidores de la Transcriptasa Inversa/sangre , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Benzothiadiazine non-nucleoside reverse transcriptase inhibitors (NNRTIs) of HIV have been synthesized via a novel process to afford active inhibitors, with the most potent compound exhibiting an IC90 = 180 nM in a whole cell assay. The 2,2-dioxide-1H-2,1,3-benzothiadiazine ring system was constructed in one step from 2-amino-5-chlorobenzonitrile.
Asunto(s)
Benzotiadiazinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Benzotiadiazinas/farmacología , VIH-1/enzimología , Humanos , Estructura Molecular , Inhibidores de la Transcriptasa Inversa/farmacologíaRESUMEN
A research program targeted toward the identification of expanded-spectrum nonnucleoside reverse transcriptase inhibitors which possess increased potency toward K103N-containing mutant human immunodeficiency virus (HIV) and which maintain pharmacokinetics consistent with once-a-day dosing has resulted in the identification of the 4-cyclopropylalkynyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 961 and DPC 963 and the 4-cyclopropylalkenyl-4-trifluoromethyl-3, 4-dihydro-2(1H)quinazolinones DPC 082 and DPC 083 for clinical development. DPC 961, DPC 963, DPC 082, and DPC 083 all exhibit low-nanomolar potency toward wild-type virus, K103N and L100I single-mutation variants, and many multiply amino acid-substituted HIV type 1 mutants. This high degree of potency is combined with a high degree of oral bioavailability, as demonstrated in rhesus monkeys and chimpanzees, and with plasma serum protein binding that can result in significant free levels of drug.
Asunto(s)
Fármacos Anti-VIH/farmacología , Transcriptasa Inversa del VIH/antagonistas & inhibidores , VIH-1/efectos de los fármacos , VIH-1/genética , Mutación/fisiología , Inhibidores de la Transcriptasa Inversa/farmacología , Sustitución de Aminoácidos/genética , Animales , Fármacos Anti-VIH/farmacocinética , Proteínas Sanguíneas/metabolismo , VIH-1/enzimología , Semivida , Humanos , Macaca mulatta , Masculino , Pan troglodytes , Unión Proteica , Inhibidores de la Transcriptasa Inversa/farmacocinética , EstereoisomerismoRESUMEN
The preparation of unsymmetrical cyclic ureas bearing novel biaryl indazoles as P2/P2' substituents was undertaken, utilizing a Suzuki coupling reaction as the key step. Compound 6i was equipotent to the lead compound of the series SE063.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Urea/química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Proteasa del VIH/efectos de los fármacos , Inhibidores de la Proteasa del VIH/farmacología , VIH-1/enzimología , Urea/farmacologíaRESUMEN
Two series of benzoxazinones differing in the aromatic substitution pattern were prepared and evaluated as HIV-1 reverse transcriptase inhibitors. The 5-fluoro (5a-d) and 6-nitro (5e-h) substituted compounds displayed activity comparable or better than Efavirenz, the lead structure of the series.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Oxazinas/química , Oxazinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Alquinos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Benzoxazinas , Ciclopropanos , Evaluación Preclínica de Medicamentos , Transcriptasa Inversa del VIH/efectos de los fármacos , Oxazinas/farmacología , Inhibidores de la Transcriptasa Inversa/química , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
Efavirenz (SUSTIVA) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here. The 5,6-difluoro (4f) and the 6-methoxy (4m) substituted benzoxazinones were determined to be equipotent, and as a result such substitution patterns will be incorporated in second generation scaffolds.
Asunto(s)
Fármacos Anti-VIH/síntesis química , VIH-1 , Oxazinas/química , Oxazinas/síntesis química , Inhibidores de la Transcriptasa Inversa/síntesis química , Alquinos , Fármacos Anti-VIH/farmacología , Benzoxazinas , Ciclopropanos , Estructura Molecular , Oxazinas/farmacología , Inhibidores de la Transcriptasa Inversa/farmacología , Relación Estructura-ActividadRESUMEN
A series of alkyl substituted P1/P1' analogs was prepared in an attempt to increase translation of the 3-aminoindazole class of HIV protease inhibitors. Increasing the lipophilicity of the P1/P1' residues dramatically improved translation of enzyme activity to antiviral activity in the whole cell assay.
Asunto(s)
Inhibidores de la Proteasa del VIH/síntesis química , Urea/análogos & derivados , Diseño de Fármacos , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/farmacología , Relación Estructura-Actividad , Urea/síntesis química , Urea/farmacologíaRESUMEN
The aspartyl dyad of free HIV-1 protease has apparent pK(a)s of approximately 3 and approximately 6, but recent NMR studies indicate that the aspartyl dyad is fixed in the doubly protonated form over a wide pH range when cyclic urea inhibitors are bound, and in the monoprotonated form when the inhibitor KNI-272 is bound. We present computations and measurements related to these changes in protonation and to the thermodynamic linkage between protonation and inhibition. The Poisson-Boltzmann model of electrostatics is used to compute the apparent pK(a)s of the aspartyl dyad in the free enzyme and in complexes with four different inhibitors. The calculations are done with two parameter sets. One assigns epsilon = 4 to the solute interior and uses a detailed model of ionization; the other uses epsilon = 20 for the solute interior and a simplified representation of ionization. For the free enzyme, both parameter sets agree well with previously measured apparent pK(a)s of approximately 3 and approximately 6. However, the calculations with an internal dielectric constant of 4 reproduce the large pKa shifts upon binding of inhibitors, but the calculations with an internal dielectric constant of 20 do not. This observation has implications for the accurate calculation of pK(a)s in complex protein environments. Because binding of a cyclic urea inhibitor shifts the pK(a)s of the aspartyl dyad, changing the pH is expected to change its apparent binding affinity. However, we find experimentally that the affinity is independent of pH from 5.5 to 7.0. Possible explanations for this discrepancy are discussed.
Asunto(s)
Inhibidores de la Proteasa del VIH/química , Protones , Concentración de Iones de Hidrógeno , Cinética , Espectroscopía de Resonancia Magnética , Oligopéptidos/farmacología , Termodinámica , Urea/antagonistas & inhibidoresRESUMEN
We have synthesized stereoisomers of cyclic urea HIV-1 protease inhibitors to study the effect of varying configurations on binding affinities. Four different synthetic approaches were used to prepare the desired cyclic urea stereoisomers. The original cyclic urea synthesis using amino acid starting materials was used to prepare three isomers. Three additional isomers were prepared by synthetic routes utilizing L-tartaric acid and D-sorbitol as chiral starting materials. A stereoselective hydroxyl inversion of the cyclic urea trans-diol was used to prepare three additional isomers. In all 9 of the 10 possible cyclic urea stereoisomers were prepared, and their binding affinities are described.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Proteasa del VIH/metabolismo , Urea/análogos & derivados , Urea/síntesis química , Fármacos Anti-VIH/química , Fármacos Anti-VIH/metabolismo , Inhibidores de la Proteasa del VIH/química , Inhibidores de la Proteasa del VIH/metabolismo , Unión Proteica , Estereoisomerismo , Relación Estructura-Actividad , Urea/química , Urea/metabolismoRESUMEN
BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.
Asunto(s)
Fármacos Anti-VIH/síntesis química , Inhibidores de la Proteasa del VIH/síntesis química , Urea/análogos & derivados , Animales , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/farmacología , Cristalografía por Rayos X , Perros , Diseño de Fármacos , VIH/efectos de los fármacos , VIH/genética , VIH/fisiología , Inhibidores de la Proteasa del VIH/farmacología , Estructura Molecular , Mutación , Unión Proteica , Urea/síntesis química , Urea/química , Urea/farmacocinética , Urea/farmacología , Replicación Viral/efectos de los fármacosRESUMEN
The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.