RESUMO
In this Letter we describe the design, synthesis, screening, and optimization of a new family of ADAMTS-5 inhibitors. These inhibitors display an original 1,2,4-triazole-3-thiol scaffold as a putative zinc binding-group. In vitro results are rationalized by in silico docking of the compounds in ADAMTS-5's crystal structure.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Proteína ADAMTS5 , Sítios de Ligação , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos , Humanos , Indicadores e Reagentes , Modelos Moleculares , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/química , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , Triazóis/química , Difração de Raios XRESUMO
Over the last decade, there has been a large effort to target aggrecanases, which are responsible for the degradation of the aggrecan in the extracellular matrix of joints, in order to hopefully lead to new treatments for osteoarthritis. Only a few inhibitors have been effective in explants or rodent models and thus only a few have reached the clinic, none of which have proven to be effective. In this article, a survey of chemical series is described, covering historical and recent inhibitors and highlighting how some of their problems were resolved, with a critical overview of the challenges encountered. A large effort should be undertaken in designing smaller compounds with higher residence times, defining new interaction sites on the aggrecanases and exploiting target flexibility.
Assuntos
Endopeptidases/metabolismo , Osteoartrite/tratamento farmacológico , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Osteoartrite/enzimologia , Osteoartrite/metabolismo , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
Osteoarthritis is a disabling disease characterized by the articular cartilage breakdown. Aggrecanases are potential therapeutic targets for the treatment of this pathology. At the starting point of this project, an acylthiosemicarbazide was discovered to inhibit aggrecanase-2. The acylthiosemicarbazide Zn binding group is also a convenient linker for library synthesis. A focused library of 920 analogs was thus prepared and screened to establish structure-activity relationships. The modification of the acylthiosemicarbazide was also explored. This strategy combining library design and discrete compounds synthesis yielded inhibitor 35, that is highly selective for aggrecanases over a panel of metalloproteases and inhibits the degradation of native fully glycosylated aggrecan. A docking study generated binding conformations explaining the structure-activity relationships.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Compostos Organometálicos/farmacologia , Semicarbazidas/química , Zinco/química , Proteínas ADAM/metabolismo , Proteína ADAMTS5 , Relação Dose-Resposta a Droga , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Humanos , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Compostos Organometálicos/química , Relação Estrutura-AtividadeRESUMO
A high throughput screen was developed to identify novel, nonsteroidal RORα agonists. Among the validated hit compounds, the 4-(4-(benzyloxy)phenyl)-5-carbonyl-2-oxo-1,2,3,4-tetrahydropyrimidine scaffold was the most prominent. Among the numerous analogues tested, compounds 8 and 9 showed the highest activity. Key structure-activity relationships (SAR) were established, where benzyl and urea moieties were both identified as very important elements to maintain the activity. Most notably, the SAR were consistent with the binding mode of the compound 8 (S-isomer) in the RORα docking model that was developed in this program. As predicted by the model, the urea moiety is engaged in the formation of key hydrogen bonds with the backbone of Tyr380 and Asp382. The benzyl group is located in a wide hydrophobic pocket. The structural relationships reported in this letter will help in further optimization of this compound series and will provide novel synthetic probes helpful for elucidation of complex RORα physiopathology.
RESUMO
The first de novo synthesis of a beta-C-naphthyl glycoside displaying a convenient functionality for subsequent transformations into complex C-aryl glycosides is reported. The synthesis of this (+/-)-beta-C-1,5-dibenzyloxynaphthyl 6,6,6-trifluoro-3-amino glycoside relies on a hyperbaric HDA reaction involving a new 2-vinylnaphthalenic dienophile.
Assuntos
Glicosídeos/síntese química , Hidrocarbonetos Fluorados/síntese química , Naftalenos/síntese química , Catálise , Técnicas de Química Combinatória , Ciclização , Glicosídeos/química , Hidrocarbonetos Fluorados/química , Estrutura Molecular , Naftalenos/química , EstereoisomerismoRESUMO
A convergent synthesis of the naturally occurring alkaloid Calothrixin B is presented, which used a regioselective hetero-Diels-Alder reaction between a "push-pull" 2-aza-diene and a N-protected 3-bromo-9H-carbazole-1,4-dione to construct the five-ring skeleton of the molecule. Protection of the indole motif with a benzyl group was unattractive for delivery of sufficient target material because the removal of the protecting group had not been high yielding. We therefore elected to temporarily protect the indole motif with a more labile benzyloxycarbonyl group. Accordingly, the synthesis of calothrixin B proceeded in 17% overall yield over 9 steps from the commercially available 1,2,3,9-tetrahydro-4H-carbazol-4-one.