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Bone Anabolic Agents (bone + anabolic_agent)
Selected AbstractsStructure,function relationship studies of PTH(1,11) analogues containing sterically hindered dipeptide mimeticsJOURNAL OF PEPTIDE SCIENCE, Issue 8 2007Nereo Fiori Abstract The N -terminal 1,34 fragment of parathyroid hormone (PTH) is fully active in vitro and in vivo and reproduces all biological responses characteristic of the native intact PTH. In order to develop safer and non-parenteral PTH-like bone anabolic agents, we have studied the effect of introducing conformationally constrained dipeptide mimetics into the N -terminal portion of PTH in an effort to generate miniaturized PTH-mimetics. To this end, we have synthesized and conformationally and biologically characterized PTH(1,11) analogues containing 3R -carboxy-6S -amino-7,5-bicyclic thiazolidinlactam (7,5-bTL), a rigidified dipeptide mimetic unit. The wild type sequence of PTH(1,11) is H-Ser-Val-Ser-Glu-Ile-Gln-Leu-Met-His-Asn-Leu-NH2. The following pseudo-undecapeptides were prepared: [Ala1, 7,5-bTL3, 4, Nle8, Arg11]hPTH(1,11)NH2 (I); [Ala1, 7,5-bTL6, 7, Nle8, Arg11]hPTH(1,11)NH2 (II); [Ala1, Nle8, 7,5-bTL9, 10, Arg11]hPTH(1,11)NH2 (III). In aqueous solution containing 20% TFE, only analogue I exhibited the typical CD pattern of the ,-helical conformation. NMR experiments and molecular dynamics calculations located the ,-helical stretch in the sequence Ile5 -His9. The dipeptide mimetic unit 7,5-bTL induces a type III ,-turn, occupying the positions i , 1 and i of the turn. Analogue II exhibited an equilibrium between a type I ,-turn and an ,-helix, and analogue III did not show any ordered structure. Biological tests revealed poor activity for all analogues (EC50 > 0.1 mM). Apparently, the relative side-chain orientation of Val2, Ile5 and Met8 can be critical for effective analogue-receptor interaction. Considering helicity as an essential property to obtain active PTH agonists, one must decorate the correctly positioned dipeptide mimetic azabicycloalkane scaffold with substitutions corresponding to the displaced amino acids. Copyright © 2007 European Peptide Society and John Wiley & Sons, Ltd. [source] Statins and osteoporosis: new role for old drugsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2006Satyawan B. Jadhav Osteoporosis is the most common bone disease, affecting millions of people worldwide and leading to significant morbidity and high expenditure. Most of the current therapies available for its treatment are limited to the prevention or slowing down of bone loss rather than enhancing bone formation. Recent discovery of statins (HMG-CoA reductase inhibitors) as bone anabolic agents has spurred a great deal of interest among both basic and clinical bone researchers. In-vitro and some animal studies suggest that statins increase the bone mass by enhancing bone morphogenetic protein-2 (BMP-2)-mediated osteoblast expression. Although a limited number of case,control studies suggest that statins may have the potential to reduce the risk of fractures by increasing bone formation, other studies have failed to show a benefit in fracture reduction. Randomized, controlled clinical trials are needed to resolve this conflict. One possible reason for the discrepancy in the results of preclinical, as well as clinical, studies is the liver-specific nature of statins. Considering their high liver specificity and low oral bioavailability, distribution of statins to the bone microenvironment in optimum concentration is questionable. To unravel their exact mechanism and confirm beneficial action on bone, statins should reach the bone microenvironment in optimum concentration. Dose optimization and use of novel controlled drug delivery systems may help in increasing the bioavailability and distribution of statins to the bone microenvironment. Discovery of bone-specific statins or their bone-targeted delivery offers great potential in the treatment of osteoporosis. In this review, we have summarized various preclinical and clinical studies of statins and their action on bone. We have also discussed the possible mechanism of action of statins on bone. Finally, the role of drug delivery systems in confirming and assessing the actual potential of statins as anti-osteoporotic agents is highlighted. [source] Wnts, bone and cancer,THE JOURNAL OF PATHOLOGY, Issue 1 2010David M Thomas Abstract The Wnt pathway plays vital roles in bone and in cancer. In this issue of The Journal of Pathology, Cai and colleagues report results that suggest that the Wnt pathway is inactivated in bone cancers, a finding that could have significant implications for the development of Wnt agonists as bone anabolic agents. While these findings are at odds with the prevailing view that the Wnt pathway is oncogenic in all systems studied to date, they remind us how complex and still poorly understood this important signalling pathway remains. At the very least, these findings should provoke debate and stimulate further research into the role of Wnt signalling in osteosarcoma. Copyright © 2009 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] An in,vitro Assay to Measure Targeted Drug Delivery to Bone MineralCHEMMEDCHEM, Issue 5 2010Wolfgang Jahnke Dr. Abstract Targeted delivery of drugs to their site of action is a promising strategy to decrease adverse effects and enhance efficacy, but successful applications of this strategy have been scarce. Human bone is a tissue with unique properties due to its high hydroxyapatite mineral content. However, with the exception of bisphosphonates, bone mineral has not been targeted in a successful clinical application of drugs that act on bone, such as anti-resorptive or bone anabolic agents. Herein we present an NMR-based in,vitro assay to measure binding affinities of small molecules to hydroxyapatite (HAP) or bone powder. Binding was shown to be specific and competitive, and the assay can be carried out in a direct binding format or in competition mode. A selection of clinically relevant bisphosphonates was ranked by their binding affinity for HAP. The binding affinity decreases in the order: pamidronate > alendronate > zoledronate > risedronate > ibandronate. The differences in binding affinities span a factor of 2.1 between pamidronate and ibandronate, consistent with previous studies. The rank order is very similar with bone powder, although the binding capacity of bone powder is smaller and binding kinetics are slower. A zoledronate derivative that lacks the central hydroxy group binds to HAP with 2.3-fold weaker affinity than zoledronate itself. Any small molecule can be analyzed for its binding to HAP or bone powder, and the binding of common bone-staining agents such as alizarin and its derivatives was confirmed in the new assay. This assay supports a strategy for targeted delivery of drugs to bone by attaching a bone-affinity tag to the active drug substance. [source] | |||||||||||||