Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.

Arsenic, chromium, and other elements of concern in fish from remote boreal lakes and rivers: Drivers of variation and implications for subsistence consumption.

Eating fish provides numerous health benefits, but it is also a dominant pathway for human exposure to contaminants. Many studies have examined mercury (Hg) accumulation in fish, but fewer have considered other elements, such as arsenic (As) and chromium (Cr). Recently, freshwater fish from several pristine boreal systems across northern Ontario, Canada, have been reported with elevated concentrations of As and Cr for reasons that are not well understood. Our goal was to investigate the ecological and environmental influences over concentrations of As, Cr, and other elements in these fish to better understand what affects metal uptake and the risk to consumers. We measured 10 elements (including As, Cr, Hg) as well as carbon (δ13C), nitrogen (δ15N), and sulfur (δ34S) stable isotopes in 388 fish from 25 lake and river sites across this remote region. These data were used to determine the effect of: 1) trophic ecology; and 2) watershed geology on piscine elemental content. Overall, most element concentrations were low, often below provincial advisory benchmarks (ABs). However, traces of Hg, As, Cr, and selenium (Se) were detected in most fish. Based on their exceedance of their respective ABs, the most restrictive elements on fish consumption in these boreal systems were Hg > As > Cr. Arsenic and Se, but not Cr concentrations were related to fish size and trophic ecology (inferred from δ13C and δ15N), suggesting bioaccumulation of the former elements. Fish with enriched δ34S values, suggestive of anadromous behaviour, had marginally lower Hg but higher Se concentrations. Modeling results suggested a strong effect of site-specific factors, though we found weak trends between piscine elemental content and geological features (e.g., mafic intrusions), potentially due to the broad spatial scale of this study. Results from this study address gaps in our understanding of As and Cr bioaccumulation and will help to inform fish consumption guidelines.

Quinazolinones and pyrido[3,4-d]pyrimidin-4-ones as orally active and specific matrix metalloproteinase-13 inhibitors for the treatment of osteoarthritis.

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.

Nuclear factor-kappaB mediated inhibition of cytokine production by imidazoline scaffolds.

The mammalian nuclear transcription factor NF-kappaB is responsible for the transcription of multiple cytokines, including the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6). Elevated levels of pro-inflammatory cytokines play an important role in the pathogenesis of inflammatory disorders such as rheumatoid arthritis (RA). Inhibition of the pro-inflammatory transcription factor NF-kappaB has therefore been identified as a possible therapeutic treatment for RA. We describe herein the synthesis and biological activity of a series of imidazoline-based scaffolds as potent inhibitors of NF-kappaB mediated gene transcription in cell culture as well as inhibitors of TNF-alpha and IL-6 production in interleukin 1 beta (IL-1beta) stimulated human blood.

Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia side effects.

Matrix metalloproteinase-13 (MMP13) is a Zn(2+)-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 structure-based 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.