RESUMO
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
Assuntos
Oxidiazóis/farmacologia , Receptores de Lisoesfingolipídeo/agonistas , Tiadiazóis/farmacologia , Animais , Encéfalo/metabolismo , Ácido Glutâmico/metabolismo , Células Hep G2 , Humanos , Ligação de Hidrogênio , Cinética , Oxidiazóis/sangue , Oxidiazóis/síntese química , Ratos , Solubilidade , Relação Estrutura-Atividade , Tiadiazóis/sangue , Tiadiazóis/síntese químicaRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.
Assuntos
Aminas/síntese química , Benzamidas/síntese química , Biomarcadores Tumorais , Descoberta de Drogas , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Aminas/química , Aminas/farmacologia , Animais , Benzamidas/química , Benzamidas/farmacologia , Benzoquinonas/síntese química , Benzoquinonas/química , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/química , Lactamas Macrocíclicas/farmacologia , Compostos Macrocíclicos/química , Camundongos , Modelos Moleculares , Estrutura Molecular , Neoplasias/tratamento farmacológico , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.
Assuntos
Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Lactamas Macrocíclicas/síntese química , Lactamas Macrocíclicas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Cristalografia por Raios X , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/química , Corantes Fluorescentes/farmacologia , Humanos , Concentração Inibidora 50 , Lactamas Macrocíclicas/química , Modelos Moleculares , Estrutura Molecular , ortoaminobenzoatos/síntese química , ortoaminobenzoatos/química , ortoaminobenzoatos/farmacologiaRESUMO
An extension of our previously reported series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. Addition of a second methyl group to the tether provided analogs that show increased potency in binding as well as cell-proliferation assays and, more importantly, are stable toward microsomes. We wish to disclose the discovery of a macrocycle which showed impressive biomarker activity 24-h post dosing and which demonstrated prolonged exposure in tumors. When studied in a lung cancer xenograft model, the compound demonstrated significant tumor size reduction.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Neoplasias Pulmonares/tratamento farmacológico , Compostos Macrocíclicos/química , Administração Oral , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Sítios de Ligação , Biomarcadores/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Camundongos , Camundongos Nus , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Ratos , Transplante HeterólogoRESUMO
A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.
Assuntos
Antineoplásicos/química , Benzamidas/química , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Benzamidas/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Proliferação de Células , Simulação por Computador , Cristalografia por Raios X , Desenho de Fármacos , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Ligação Proteica , Relação Estrutura-AtividadeRESUMO
A series of pyrazolo[1,5-alpha]pyrimidine analogs has been prepared and found to be potent and selective B-Raf inhibitors. Molecular modeling suggests they bind to the active conformation of the enzyme.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
A series of alpha-sulfone piperidine hydroxamate TACE inhibitors 11a-n bearing a quinolinyl methyl P1' group was prepared, and their activity was compared to analogous alpha- and beta-sulfone piperidine hydroxamates with a butynyloxy P1' group. The quinolinyl methyl P1' group affords increased inhibitory enzyme activity relative to the corresponding butynyloxy P1' analogs in the alpha-sulfone piperidine hydroxamate series, and greater selectivity than the corresponding butynyloxy P1' analogs in the beta-sulfone piperidine hydroxamate series.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/síntese química , Piperidinas/química , Inibidores de Proteases/síntese química , Sulfonas/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Animais , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Camundongos , Piperidinas/síntese química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Sulfonas/síntese químicaRESUMO
As part of our research effort to discover B-Raf kinase inhibitors, we prepared a series of C-3 substituted N-(3-(pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-3-(trifluoromethyl)benzamides. X-ray crystallography studies revealed that one of the more potent inhibitors (10n) bound to B-Raf kinase without forming a hinge-binding hydrogen bond. With basic amine residues appended to C-3 aryl residues, cellular activity and solubility were enhanced over previously described compounds of this class.
Assuntos
Benzamidas/farmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Benzamidas/síntese química , Benzamidas/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pirazóis/síntese química , Pirazóis/química , Pirimidinas/síntese química , Pirimidinas/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel series of pyrazolo[1,5-a]pyrimidines bearing a 3-hydroxyphenyl group at C(3) and substituted tropanes at C(7) have been identified as potent B-Raf inhibitors. Exploration of alternative functional groups as a replacement for the C(3) phenol demonstrated indazole to be an effective isostere. Several compounds possessing substituted indazole residues, such as 4e, 4p, and 4r, potently inhibited cell proliferation at submicromolar concentrations in the A375 and WM266 cell lines, and the latter two compounds also exhibited good therapeutic indices in cells.
Assuntos
Antineoplásicos/química , Inibidores Enzimáticos/química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/química , Piridinas/química , Pirimidinas/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Pirazóis/farmacologia , Piridinas/farmacologia , Pirimidinas/farmacologiaRESUMO
Potent 3,4-disubstituted benzofuran P1' MMP-13 inhibitors have been prepared. Selectivity over MMP-2 was achieved through a substituent at the C4 position of the benzofuran P1' moiety of the molecule. By replacing a backbone benzene with a pyridine and valine with threonine, compounds (e.g., 44) with greatly reduced plasma protein binding were also obtained.
Assuntos
Benzofuranos/química , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/química , Animais , Benzofuranos/síntese química , Benzofuranos/farmacologia , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ligação Proteica , Coelhos , Albumina Sérica/química , Relação Estrutura-AtividadeRESUMO
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sulfonamidas/química , Triptofano/análogos & derivados , Proteína ADAM17 , Animais , Ácidos Carboxílicos/química , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Triptofano/síntese química , Triptofano/química , Triptofano/farmacologiaRESUMO
The serine/threonine kinase AKT/PKB plays a critical role in cancer and represents a rational target for therapy. Although efforts in targeting AKT pathway have accelerated in recent years, relatively few small molecule inhibitors of AKT have been reported. The development of selective AKT inhibitors is further challenged by the extensive conservation of the ATP-binding sites of the AGC kinase family. In this report, we have conducted a high-throughput screen for inhibitors of activated AKT1. We have identified lactoquinomycin as a potent inhibitor of AKT kinases (AKT1 IC(50), 0.149 +/- 0.045 micromol/L). Biochemical studies implicated a novel irreversible interaction of the inhibitor and AKT involving a critical cysteine residue(s). To examine the role of conserved cysteines in the activation loop (T-loop), we studied mutant AKT1 harboring C296A, C310A, and C296A/C310A. Whereas the ATP-pocket inhibitor, staurosporine, indiscriminately targeted the wild-type and all three mutant-enzymes, the inhibition by lactoquinomycin was drastically diminished in the single mutants C296A and C310A, and completely abolished in the double mutant C296A/C310A. These data strongly implicate the binding of lactoquinomycin to the T-loop cysteines as critical for abrogation of catalysis, and define an unprecedented mechanism of AKT inhibition by a small molecule. Lactoquinomycin inhibited cellular AKT substrate phosphorylation induced by growth factor, loss of PTEN, and myristoylated AKT. The inhibition was substantially attenuated by coexpression of C296A/C310A. Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors.
Assuntos
Cisteína/metabolismo , Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Trifosfato de Adenosina/farmacologia , Regulação Alostérica/efeitos dos fármacos , Animais , Catálise/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/química , Humanos , Cinética , Naftoquinonas/química , Naftoquinonas/farmacologia , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Quinases/metabolismo , Capuzes de RNA/metabolismo , Ratos , Relação Estrutura-Atividade , Especificidade por Substrato/efeitos dos fármacos , Serina-Treonina Quinases TOR , Fatores de TempoRESUMO
INTRODUCTION: Tumor necrosis factor-alpha (TNFalpha) participates in many inflammatory processes. TNFalpha modulators show beneficial effects for the treatment of many diseases including rheumatoid arthritis. The purpose of this study was to validate a rat pharmacokinetic/pharmacodynamic (PK/PD) model for rapid assessment of drug candidates that intended to interrupt TNFalpha synthesis or release. METHODS: Rats received intravenous (IV) or oral administrations of test article or dose vehicle, followed by LPS challenge. Plasma levels of test article and TNFalpha were determined. The areas under the concentration-time curves (AUC(drug) and AUC(TNFalpha)) were calculated. The overall percentage of inhibition on TNFalpha release in vivo was calculated by comparing AUC(TNFalpha) of the test article treated group against that for the vehicle control group. RESULTS: The dosing vehicles tested in this study did not increase plasma TNFalpha level. At IV dose of up to 100 microg/kg, LPS did not alter the pharmacokinetics of the compound tested. Using a selective TNFalpha converting enzyme (TACE) inhibitor as model compound, this PK/PD model demonstrated its ability to correlate plasma test article concentration with its biological activity of lowering the LPS-induced TNFalpha plasma levels in vivo. DISCUSSION: A rat PK/PD model for evaluation of the effect of drug candidates on LPS-induced TNFalpha synthesis and/or release has been investigated. This model provides integrated information on pharmacokinetics and in vivo potency of the test articles.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Sulfonamidas/farmacologia , Fator de Necrose Tumoral alfa/biossíntese , Proteína ADAM17 , Animais , Feminino , Humanos , Modelos Biológicos , Ratos , Ratos Endogâmicos Lew , Sulfonamidas/farmacocinéticaRESUMO
Inhibitors of matrix metalloprotease (MMP)-13 and tumor necrosis factor-alpha converting enzyme (TACE) have been highly sought as potential therapeutic agents for the treatment of osteoarthritis and rheumatoid arthritis, respectively. This review focuses on the published literature on these inhibitors from 2001 to mid-2003. Significant advances have been reported in the design and synthesis of potent and selective inhibitors of MMP-13 using hydroxamic acid and non-hydroxamate zinc chelators on a variety of scaffolds. TACE inhibitors based on variations of known MMP inhibitors scaffolds and novel designs have been reported. Selectivity profiles for these inhibitors range from broad-spectrum to TACE-specific. Future clinical studies on these and other inhibitors will determine which MMP, or set of MMPs, must be inhibited for efficacy and long-term safety.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/química , Inibidores de Proteases/síntese química , Proteínas ADAM , Proteína ADAM17 , Animais , Artrite Reumatoide/tratamento farmacológico , Quelantes , Desenho de Fármacos , Humanos , Ácidos Hidroxâmicos/síntese química , Metaloproteinase 13 da Matriz , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Relação Estrutura-Atividade , ZincoRESUMO
Three different classes of aryl hydroxamic acid scaffolds have been explored and provided potent inhibitors of MMP-1, -2, -9, -13 and TACE. Structure-based design has allowed the evolution of these inhibitors from broad spectrum inhibitors into compounds that are more selective for MMPs relevant to particular disease states. Aryl hydroxamates selective for MMP-9, MMP-13 and TACE have been disclosed that may aid in the study of the physiological role of these enzymes. Furthermore, the different selectivity profiles offered by these MMP/TACE inhibitors may allow the determination of which metalloprotease, or group of metalloproteases, must be inhibited for the safe, long-term treatment of osteoarthritis, rheumatoid arthritis and cancer. Some of these compounds have demonstrated useful biological activity in efficacy models relevant to osteoarthritis and rheumatoid arthritis and are therefore potential clinical candidates.
Assuntos
Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Proteínas ADAM , Proteína ADAM17 , Animais , Desenho de Fármacos , HumanosRESUMO
A series of 4-alkynyloxy phenyl sulfanyl, sulfinyl and sulfony alkyl and piperidine-4-carboxylic acid hydroxamides were synthesized. Their structure-activity relationships, against tumor necrosis factor-alpha (TACE) and matrix metalloproteinase (MMP) inhibitor activities, are presented by investigating the oxidation state on sulfur and altering the P1' substituent. The sulfonyl derivatives 20-24 carrying a 4-butynyloxy moiety were selective TACE inhibitors over the MMPs tested. The sulfinyl derivatives showed a preference for a specific oxidation on sulfur as in compounds 25-28. The selectivity over MMPs was also demonstrated in the sulfonyl series. The enhanced cellular activity was achieved upon incorporating a butynyloxy substituent in the piperidene series. Compounds 64 and 65 were potent inhibitors of TNF-alpha release in the mouse at 100 mg/kg po.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Sulfetos/síntese química , Sulfonas/síntese química , Sulfóxidos/síntese química , Proteínas ADAM , Proteína ADAM17 , Animais , Cristalografia por Raios X , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Técnicas In Vitro , Camundongos , Modelos Moleculares , Estrutura Molecular , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Oxirredução , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacologia , Relação Estrutura-Atividade , Sulfetos/química , Sulfetos/farmacologia , Sulfonas/química , Sulfonas/farmacologia , Sulfóxidos/química , Sulfóxidos/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. In our preceding paper, we have reported on a series of novel and orally active N-hydroxy-alpha-phenylsulfonylacetamide derivatives. However, these compounds had two drawbacks (moderate selectivity and chirality issues). To circumvent these two problems, a series of novel and orally active N-substituted 4-benzenesulfonylpiperidine-4-carboxylic acid hydroxyamide derivatives have been synthesized. The present paper deals with the synthesis and SAR of these compounds. Among the several compounds synthesized, derivative 55 turned out to be a potent, selective, and an orally active MMP inhibitor in the clinically relevant advanced rabbit osteoarthritis model. Detailed pharmacokinetics and metabolism data are described.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Piperidinas/síntese química , Inibidores de Proteases/síntese química , Sulfonas/síntese química , Proteínas ADAM , Proteína ADAM17 , Administração Oral , Animais , Sítios de Ligação , Bioensaio , Cartilagem/efeitos dos fármacos , Cartilagem/enzimologia , Bovinos , Cristalografia por Raios X , Diálise , Cães , Haplorrinos , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Masculino , Metaloproteinase 13 da Matriz , Metaloproteinases da Matriz/química , Metaloendopeptidases/antagonistas & inibidores , Camundongos , Modelos Moleculares , Piperidinas/farmacocinética , Piperidinas/farmacologia , Inibidores de Proteases/farmacocinética , Inibidores de Proteases/farmacologia , Coelhos , Ratos , Relação Estrutura-Atividade , Sulfonas/farmacocinética , Sulfonas/farmacologiaRESUMO
Novel indazolylpyrazolo[1,5-a]pyrimidine analogues have been prepared and found to be extremely potent type I B-Raf inhibitors. The lead compound shows good selectivity against a panel of 60 kinases, possesses a desirable pharmacokinetic profile, and demonstrates excellent in vivo antitumor efficacy in B-Raf mutant xenograft models.
Assuntos
Antineoplásicos/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Indazóis/síntese química , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Pirazóis/síntese química , Pirimidinas/síntese química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indazóis/química , Indazóis/farmacologia , Camundongos , Modelos Moleculares , Mutação , Transplante de Neoplasias , Proteínas Proto-Oncogênicas B-raf/genética , Pirazóis/química , Pirazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Transplante HeterólogoRESUMO
The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.
Assuntos
Antineoplásicos/síntese química , Cisteína/metabolismo , Lactonas/síntese química , Proteína Oncogênica v-akt/antagonistas & inibidores , Piranos/síntese química , Alquilação , Antineoplásicos/química , Antineoplásicos/farmacologia , Biomarcadores/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Lactonas/química , Lactonas/farmacologia , Naftoquinonas/síntese química , Naftoquinonas/química , Naftoquinonas/farmacologia , Piranos/química , Piranos/farmacologia , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of beta-sulfonyl hydroxamate TACE inhibitors, bearing a butynylamino or a butynyloxy P1' group, was designed and synthesized. Of the compounds investigated, 22 has excellent potency against isolated TACE enzyme, shows good selectivity over MMP-2 and MMP-13, and oral activity in an in vivo mouse model of TNF-alpha production.