RESUMO
Kallikrein 7 (KLK7) is a chymotrypsin-like serine protease with established roles in skin diseases like the rare Netherton syndrome, an overdesquamating and inflammatory condition, but also common atopic dermatitis, and a potential drug target for these and possibly other diseases. Nevertheless, tools to determine the active KLK7 enzyme are not available. Here, a mixed alkyl aryl phosphonate quenched activity-based probe that detects the active KLK7 was developed and evaluated in vitro. This KLK7-qABP can potentially be used to monitor KLK7 activity in vivo.
Assuntos
CalicreínasRESUMO
We applied a new in silico approach for using protease-substrate motifs to design a kallikrein 7 (KLK7)-specific phosphonate activity-based probe (ABP) to quantify the active KLK7 in situ. Epidermal application of the ABP-inhibitor on Spink5-/-Klk5-/- mice, a Netherton syndrome model, reversed disease hallmarks, providing preclinical proof-of-concept for using ABPs as theranostics.
Assuntos
Simulação por Computador , Calicreínas/metabolismo , Sondas Moleculares/metabolismo , Dermatopatias/diagnóstico , Dermatopatias/terapia , Dermatopatias/metabolismoRESUMO
The important requirement for approval of a new drug, in case it happens to be chiral, is that both enantiomers of the drug should be studied in detail, which has led synthetic organic and medicinal chemists to focus their attention on the development of new methods for asymmetric synthesis especially of relevant saturated N-heterocycles. On the other hand, the piperazine ring, besides defining a major class of saturated N-heterocycles, has been classified as a privileged structure in medicinal chemistry, since it is more than frequently found in biologically active compounds including several marketed blockbuster drugs such as Glivec (imatinib) and Viagra (sildenafil). Indeed, 13 of the 200 best-selling small molecule drugs in 2012 contained a piperazine ring. Nevertheless, analysis of the piperazine substitution pattern reveals a lack of structural diversity, with almost every single drug in this category (83%) containing a substituent at both the N1- and N4-positions compared to a few drugs having a substituent at any other position (C2, C3, C5, and C6). Significant chemical space that is closely related to that known to be biologically relevant, therefore, remains unexplored. In order to explore this chemical space, efficient and asymmetric syntheses of carbon-substituted piperazines and related heterocycles must be designed and developed. Initial, recent efforts toward the implementation of this particular target are in fact the subject of this review.
RESUMO
[reaction: see text] A variant of the Huisgen 1,3-dipolar cycloaddition reaction provides a new and convenient functionalization of fullerenes. This method complements the widely used Prato and Bingel-Hirsch reactions. The derived, highly functionalized cyclopentenone and cyclopentenamine fullerene compounds upon hydrolysis are suitable for further functionalization and may serve well in the synthesis of new C60 derivatives possessing uncommon and interesting properties.
RESUMO
Given the proposed involvement of VLA-4 in inflammatory processes, a program to identify orally active VLA-4 antagonists was initiated. Herein, we report the discovery of a N-tetrahydrofuroyl-(L)-phenylalanine derivative (17) and related analogues as potent VLA-4 antagonists with good oral bioavailability.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Fenilalanina/análogos & derivados , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Relação Dose-Resposta a Droga , Furanos/síntese química , Furanos/química , Furanos/farmacocinética , Furanos/farmacologia , Meia-Vida , Concentração Inibidora 50 , Macaca mulatta , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.
Assuntos
Dipeptídeos/farmacocinética , Integrina alfa4beta1/antagonistas & inibidores , Animais , Disponibilidade Biológica , Dipeptídeos/síntese química , Dipeptídeos/química , Cães , Haplorrinos , Concentração Inibidora 50 , Taxa de Depuração Metabólica , Fenilalanina , Ratos , Ratos Sprague-Dawley , Ovinos , Relação Estrutura-Atividade , Sulfonas , Molécula 1 de Adesão de Célula Vascular/efeitos dos fármacosRESUMO
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl- and (L)-azetidyl-beta-biaryl beta-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins.
Assuntos
Integrina alfa4beta1/antagonistas & inibidores , Propionatos/síntese química , Administração Oral , Alanina/síntese química , Alanina/farmacocinética , Alanina/farmacologia , Disponibilidade Biológica , Humanos , Concentração Inibidora 50 , Células Jurkat , Taxa de Depuração Metabólica , Propionatos/farmacocinética , Propionatos/farmacologia , Ligação Proteica , Relação Estrutura-Atividade , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties.