Biomedical subjects
Publications and source records attributed to F C Nelson.
The SAR of a series of potent sulfonamide hydroxamate TACE inhibitors bearing novel acetylenic P1' groups was explored. In particular, compound 4t bearing a butynyloxy P1' moiety has excellent in vitro potency against isolated TACE enzyme and in cells, good selectivity over MMP-1 and oral activity in an in vivo model of TNF-alpha production.
Anthranilic acid derivatives bearing basic amines were prepared and evaluated in vitro and in vivo as inhibitors of MMP-1, MMP-9, MMP-13, and TACE. Piperazine 4u has been identified as a potent, selective, orally active inhibitor of MMP-9 and MMP-13.
A novel series of anthranilic acid-based inhibitors of MMP-1, MMP-9, MMP-13, and TACE was prepared and evaluated. Selective inhibitors of MMP-9, MMP-13, and TACE were identified, including the potent, orally active MMP-13 inhibitor 4p.
Heteroaryl and cycloalkyl sulfonamide-hydroxamic acid MMP inhibitors were investigated. Of these, the pyridyl analogue 2 is the most potent and selective inhibitor of MMP-9 and MMP-13 in vitro.
Experimental evidence confirms that the matrix metalloproteinases (MMPs) play a fundamental role in a wide variety of pathologic conditions that involve connective tissue destruction including osteoarthritis and rheumatoid arthritis, tumor metastasis and angiogenesis, corneal ulceration, multiple sclerosis, periodontal disease, and atherosclerosis. Modulation of MMP regulation is possible at several biochemical sites, but direct inhibition of enzyme action provides a particularly attractive target for therapeutic intervention. Hypotheses concerning inhibition of specific MMP(s) with respect to disease target and/or side-effect profile have emerged. Examples are presented of recent advances in medicinal chemistry approaches to the design of matrix metalloproteinase inhibitors (MMPIs), approaches that address structural requirements and that influence potency, selectivity, and bioavailability. Two important approaches to the design, synthesis, and biological evaluation of MMPIs are highlighted: (1) the invention of alternatives to hydroxamic acid zinc chelators and (2) the construction of nonpeptide scaffolds. One current example in each of these two approaches from our own work is described.
A novel series of rapamycin derivatives with modifications in the C(22)-C(27) region has been prepared. These compounds are evaluated for their ability to prevent ring fragmentation while still retaining immunosuppressive capabilities.
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Little is known of the structural changes in mild asthma. We have studied the light and electron microscopic structure of lobar bronchial biopsies taken at fiberoptic bronchoscopy from 11 atopic asthmatics, four of whom were symptomatic and seven of whom were asymptomatic. The former and three of the latter had bronchial hyperresponsiveness to methacholine (PC20 less than 4 mg/ml). Quantitative comparisons were made with biopsies from ten control subjects with normal airway reactivity; five had hay fever and five were nonatopic healthy volunteers. Complete absence of surface epithelium was found in three cases of symptomatic asthma, and stratified squamous epithelium was present in the fourth. A biopsy from one of the healthy control subjects had also lost its surface epithelium. The degree of epithelial loss in all subjects correlated with the degree of airway reactivity (rs = 0.67, p less than 0.001). The reticular lamina of the epithelial basement membrane showed a trend toward thickening in the seven hyperreactive asthmatics (p less than 0.001: median test). There was a tendency to high numbers of inflammatory cells in the lamina propria, but not in the submucosa, of asthmatics, but the differences between groups did not achieve statistical significance. There were significant alterations (px2 less than 0.001) in the proportions of each type of inflammatory cell found in the lamina propria and submucosa of symptomatic asthmatics: an increase of irregularly shaped lymphocytes contributed most to the observed alteration. Where surface epithelium was present, intraepithelial lymphocytes formed the major proportion of intraepithelial "migratory" cells: 64% in normal control subjects, 78% in subjects with hay fever, and 87% in asymptomatic asthmatics.(ABSTRACT TRUNCATED AT 250 WORDS)
Bovine mastitis caused by Mycoplasma agalactiae subsp. bovis was first diagnosed in 16 of 55 cows in an Ontario herd in Feburary 1972. A total of 182 of 598 (30.4%) cows from 33 of 64 (51.5%) farms in widely separated areas of the province were culturally positive. Herd incidence varied from 15 to 40% with one closed herd having an incidence of 61%. Four herds were investigated culturally and serologically by the growth inhibition test for 15 months. In the acute phase the organism was present in the milk in extremely high numbers and could still be isolated from a few cows after eight to 12 months. The sera from 89.5% of the animals with clinical mycoplasma mastitis produced a zone of surface "film" and/or colony inhibition and some cows remained positive for six to 12 months. The disease was experimentally reproduced with a pure culture of the organism isolated from the milk of a cow from one of the herds.
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