New Biology

The standard model for the preclinical development of anti-osteoporosis therapies is the ovariectomized (OVX) rat. However, Cat K inhibitors developed specifically against the human enzyme are generally significantly less potent ( 2-orders of magnitude) against the rat and mouse enzymes than against human Cat K [9]. This loss of potency towards the rodent enzymes, which is consistent with their low sequence homology, therefore restricts the use of 

A more long-term rabbit model of estrogen deficiency has also been recently described in which adult OVX rabbits (7 months) were treated with the Cat K inhibitor L-006235 (12) at 0,2,10 mg/kg, or ALN (0.125 mg/kg, 3x/wk) for 27 weeks. OVX resulted in an 11.5% vertebral bone loss compared to sham-operated controls. Both the high dose of L-006235 and ALN completely prevented this bone loss, whereas the low dose of L-006235 produced a partial response [19]. 

The mechanism of this effect was addressed in a study in which 2-5 days treatment of female cynomolgus monkeys with relacatib transiently caused a 2-3-fold increase in plasma levels of parathyroid hormone (PTH, a bone anabolic agent) post-dosing compared to vehicle-treated animals [24]. 

The evidence for the utility of Cat K inhibition in the treatment of osteoporosis is compelling, but there is mounting evidence that this enzyme may also play a role in other pathologies. Although Cat K is highly expressed in osteoclasts, more recently its expression has been documented in a number of other tissues including, but not limited to, cartilage [25], atherosclerotic plaques [26], adipose 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

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Loschen, G., and Chance, B. (1971). Rapid kinetic studies of the light emitting protein aequorin. Nature New Biology 233 273-274. 

Fluxes of continental dust preserved in ice cores of Greenland and Antarctica suggest a 30-fold increase in dust flux during the last Glacial Maximum. Dramatic increases in new biological production in the HNLC regions may have resulted, resulting in the draw-down of atmospheric CO2 (Martin, 1990). 

The United States occupies the preeminent scientific position in the "new" biology. If America is to derive the maximum benefit of its investment in basic biological research—whether in the form of better health, improved agriculture, a cleaner environment, or more efficient production of chemicals—it must also assume a preeminent position in biochemical and biomedical engineering. This can be accomplished by carrying out generic research in the following areas ... 

Aebersold R, Hood LE, Watts ID. Equipping scientists for the new biology. Nat Biotechnol 2000 18 359. 

Brown, P., Goldfarb, L.G. and Gajdusek, D.C. (1991b). The new biology of spongiform encephalopathy infectious amyloidosis with a genetic twist. Lancet 337, 1019-1022. 

The biology of the histamine H3 receptor has been detailed in several recent reviews and will not be discussed in great detail here [1-4]. Rather, we intend to draw attention to the major new biological and medicinal chemistry insights that have emerged in the histamine H3 research community over the last couple of years. 

Although the basic function of the H3 receptor has been known for over two decades, recent years have witnessed a spate of new biological insights, some of which are of particular interest to the medicinal chemist. 

Sala, N Fontcuberta, J., and Rutllant, M. L., New biological concepts on coagulation inhibi-tiors. Intensive Care Med. 19(Suppl 1), S3-S7 (1993). 

Liebler, D. C. Introduction to Proteomics Tools for the New Biology. Totowa, NJ Humana Press, 2002. 

Since the first description was only two decades ago, combinatorial biosynthesis has advanced from a limited set of proof-of-principle experiments into a more mature scientific discipline. To reach the maximal potential of natural product structural diversity, the combination of this approach with other established and emerging technologies will ultimately provide access to a rich variety of unnatural natural products with improved properties or new biological activities for future drug discovery and development. 

Products of this type seem to protect the humus from rapid incorporation into new biological processes. Additional factors that appear to be associated with the accumulation of organic matter in Mollisols are high exchange capacities, saturation with calcium, an abundance of mineral colloids and a high content of minerals of the smectite group (Fenton, 1983). 

Broder S, Venter JC. Whole genomes the foundation of new biology and medicine. Curr Opin Biotechnol 2000 11[6] 581 585. 

Pyridazines continued to play a central role in the construction of new biologically active compounds. 2,7-Dihydro-3//-pyridazino 5,4,3-17 acridin-3-ones were synthesized as cytotoxic agents <05BMC1969> and 6-(5-chloro-3-methylbenzofuran-2-sulfonyl)-2//-... 

Patel AM, Moreland LW (2010) Certolizumab pegol a new biologic targeting rheumatoid arthritis. Expert Rev Clin Immunol 6 855-866... 

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