Matrix metalloproteinase-13 (MMP13) is a Zn2؉ -dependent protease that catalyzes the cleavage of type II collagen, the main structural protein in articular cartilage. Excess MMP13 activity causes cartilage degradation in osteoarthritis, making this protease an attractive therapeutic target. However, clinically tested MMP inhibitors have been associated with a painful, joint-stiffening musculoskeletal side effect that may be due to their lack of selectivity. In our efforts to develop a disease-modifying osteoarthritis drug, we have discovered MMP13 inhibitors that differ greatly from previous MMP inhibitors; they do not bind to the catalytic zinc ion, they are noncompetitive with respect to substrate binding, and they show extreme selectivity for inhibiting MMP13. By structurebased drug design, we generated an orally active MMP13 inhibitor that effectively reduces cartilage damage in vivo and does not induce joint fibroplasias in a rat model of musculoskeletal syndrome side effects. Thus, highly selective inhibition of MMP13 in patients may overcome the major safety and efficacy challenges that have limited previously tested non-selective MMP inhibitors. MMP13 inhibitors such as the ones described here will help further define the role of this protease in arthritis and other diseases and may soon lead to drugs that safely halt cartilage damage in patients.The National Institutes of Health has estimated that more than 20 million adults in the United States suffer from osteoarthritis (OA), 3 a debilitating disease in which the protective cushion of cartilage is destroyed, resulting in pain and reduced mobility. A critical step in OA pathology is breakdown of the main structural protein of articular cartilage, type II collagen. This triple helical protein is resistant to most proteases but is efficiently recognized and degraded by the Zn 2ϩ -dependent enzyme, collagenase-3, known as matrix metalloproteinase-13 (MMP13) (1-3). MMP13 catalyzes the hydrolysis of type II collagen at a unique site resulting in 3 ⁄4-and 1 ⁄4-length polypeptide products (2-6). MMP13 is not found in normal adult tissues but is expressed in the joints and articular cartilage of OA patients (4 -8). In addition, regulated expression of human MMP13 in hyaline and joint cartilages induces OA in genetically modified mice (9). Furthermore, a MMP inhibitor that preferentially inhibits MMP13 has been shown to block the degradation of explanted human osteoarthritic cartilage (5). Based on these findings, it is likely that MMP13 is the direct cause of irreversible cartilage damage in OA.The clinical development of drugs that inhibit the actions of MMPs has been plagued by the association of a painful, joint-stiffening tendonitis-like side effect, termed "musculoskeletal syndrome" (MSS), with these inhibitors (10, 11). Such joint side effects are not unique to humans. Rats dosed with non-selective MMP inhibitors (i.e. compounds that inhibit several or all MMPs) also display MSS-like side effects such as soft tissue fibroplasias, inflammation, and pain (...

Nanomedicines have evolved into various forms including dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles since their first launch in the market. Widely highlighted benefits of nanomedicines over conventional medicines include superior efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profiles of pharmaceutical ingredients. Especially, various kinetic characteristics of nanomedicines in body are further influenced by their formulations. This review provides an updated understanding of nanomedicines with respect to delivery and pharmacokinetics. It describes the process and advantages of the nanomedicines approved by FDA and EMA. New FDA and EMA guidelines will also be discussed. Based on the analysis of recent guidelines and approved nanomedicines, key issues in the future development of nanomedicines will be addressed.

Quinazolinones 8 and pyrido[3,4-d]pyrimidin-4-ones 9 as orally active and specific matrix metalloproteinase-13 inhibitors were discovered for the treatment of osteoarthritis. Starting from a high-through-put screening (HTS) hit thizolopyrimidin-dione 7, we obtained two chemotypes, 8 and 9, using computer-aided drug design (CADD) and methodical structure-activity relationship (SAR) studies. They occupy the unique S 1'-specificity pocket and do not bind to the Zn(2+) ion. Some pyrido[3,4-d]pyrimidin-4-ones, such as 10a, possess favorable absorption, distribution, metabolism, and elimination (ADME) and safety profiles. 10a effectively prevents cartilage damage in rabbit animal models of osteoarthritis without inducing musculoskeletal side effects when given at extremely high doses to rats.

Colon targeted drug delivery systems have gained a great deal of attention as potential carriers for the local treatment of colonic diseases with reduced systemic side effects and also for the enhanced oral delivery of various therapeutics vulnerable to acidic and enzymatic degradation in the upper gastrointestinal tract. In recent years, the global pharmaceutical market for biologics has grown, and increasing demand for a more patient-friendly drug administration system highlights the importance of colonic drug delivery as a noninvasive delivery approach for macromolecules. Colon-targeted drug delivery systems for macromolecules can provide therapeutic benefits including better patient compliance (because they are pain-free and can be self-administered) and lower costs. Therefore, to achieve more efficient colonic drug delivery for local or systemic drug effects, various strategies have been explored including pH-dependent systems, enzyme-triggered systems, receptor-mediated systems, and magnetically-driven systems. In this review, recent advancements in various approaches for designing colon targeted drug delivery systems and their pharmaceutical applications are covered with a particular emphasis on formulation technologies.

No abstract