Objective. Matrix metalloproteinases (MMPs) have long been considered excellent targets for osteoarthritis (OA) treatment. However, clinical utility of broad-spectrum MMP inhibitors developed for this purpose has been restricted by dose-limiting musculoskeletal side effects observed in humans. This study was undertaken to identify a new class of potent and selective MMP-13 inhibitors that would provide histologic and clinical efficacy without musculoskeletal toxicity.Methods. Selectivity assays were developed using catalytic domains of human MMPs. Freshly isolated bovine articular cartilage or human OA cartilage was used in in vitro cartilage degradation assays. The rat model of monoiodoacetate (MIA)-induced OA was implemented for assessing the effects of MMP-13 inhibitors on cartilage degradation and joint pain. The surgical medial meniscus tear model in rats was used to evaluate the chondroprotective ability of MMP-13 inhibitors in a chronic disease model of OA. The rat model of musculoskeletal side effects (MSS) was used to assess whether selective MMP-13 inhibitors have the joint toxicity associated with broad-spectrum MMP inhibitors.Results. A number of non-hydroxamic acidcontaining compounds that showed a high degree of potency for MMP-13 and selectivity against other MMPs were designed and synthesized. Steady-state kinetics experiments and Lineweaver-Burk plot analysis of rate versus substrate concentration with one such compound, ALS 1-0635, indicated linear, noncompeti-
Ein vielversprechender Ansatz für die Tumortherapie: Mit dem seco‐CBI‐Q‐Galactosid 1 wurde ein neues hochwirksames Prodrug für eine selektive Tumortherapie unter Verwendung des ADEPT‐Ansatzes entwickelt, das sehr gute präklinische Ergebnisse bei der Behandlung eines humanen Lungenkarzinoms im SCID‐Maus‐Modell zeigt (siehe Bild; Lungengewebe nach (A) und vor Behandlung (B)).
This review is a survey of two approaches for a selective anticancer therapy that are based on a specific cleavage of specially designed non-toxic prodrugs with the liberation of a cytotoxic compound either by antibody-enzyme conjugates targeted to tumor-associated antigens or by acid-catalyzed hydrolysis of the prodrugs due to the increased concentration of hydronium ions in malignant tissue under hyperglycemic conditions. Herein, the design, synthesis and the biological testing of prodrugs are described.
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