“…This finding is in accordance with a report that certain (dialkoxyaryl)hydroxamic acids are potent PDE4 inhibitors . The dialkoxy substitution pattern, however, resulted in a dramatic loss of MMP activity, thereby revealing an apparent pharmacophore “switch” between the mono- and dimethoxyphenyl analogues of this template . Throughout our work with this template, the suppressive effect of dialkoxy substitution upon MMP inhibitory activities was so dominant that the monoalkoxy pharmacophore was required to maintain potency against the MMPs.…”
“…This finding is in accordance with a report that certain (dialkoxyaryl)hydroxamic acids are potent PDE4 inhibitors . The dialkoxy substitution pattern, however, resulted in a dramatic loss of MMP activity, thereby revealing an apparent pharmacophore “switch” between the mono- and dimethoxyphenyl analogues of this template . Throughout our work with this template, the suppressive effect of dialkoxy substitution upon MMP inhibitory activities was so dominant that the monoalkoxy pharmacophore was required to maintain potency against the MMPs.…”
“…Hydroxamic acid library 1.3 was designed and synthesized at Rhone-Poulenc Rorer following in-house observations that N -sulfonylamino hydroxamates i and dihydroisoxozole hydroxamates ii are inhibitors of MMPs and phosphodiesterase-4 (PDE4), respectively (Figure ) . The apparent SAR data suggested that the two mechanistically distinct enzymes may share common pharmacophore elements as depicted in iii .…”
“…It would be of interest to determine whether a similar SAR trend would be observed among enzymes of the same species. 2 MMP and PDE4 selective inhibitors from the hydroxamate library 1.3 …”
“…A total of 86 citations were compiled covering the years 1992 through 1997. In this 1998 annual update, there are 74 new citations, − nearly equivalent to the cumulative total of published biologically active libraries for the preceding six years. This past year, more so than any other, was marked by the coapplication of library design and synthesis with molecular modeling and structure-based design.…”
An exhaustive compilation of biologically active libraries covering the years 1992-1997 was presented in a previous review [1a]. In that review, libraries were divided among 4 major categories, including those active against proteases, non-proteolytic enzymes, Gprotein coupled receptors, and non-G-protein coupled receptors. A generic structure for each library was provided as well as the structure of the most active member. The number of biologically active libraries reported in the literature during this time period (86 total) represents <25% of the total number of published library constructs. Disclosure of library synthesis without accompanying screening data is a more common occurrence. Because these types of libraries are equally important to the practicing combinatorial chemist, it was thought that a comprehensive listing of such libraries spanning the years 1992-1997 would be a useful supplement to the previous review [1a,b].Library constructs [2-248] listed herein are relegated to one of five tables. Table 1 is entitled 'Scaffold derivatization' and includes all constructs in which a multi-functional scaffold is modified in some fashion to create a library. An example of a construct found in Table 1 would be the sequential addition of three nucleophiles to trichloropyrimidine. Table 2, entitled 'Acyclic synthesis', lists all linear constructs such as those derived from multi-component Ugi condensations.
“…Collagenase, stromelysin and gelatinase were of high interest for the potential treatment of rheumatoid arthritis. In addition hydroxamic acid MMP inhibitors can inhibit the production of tumor necrosis factor (TNF-a), a pro-inflammatory cytokine involved in the development of several inflammatory, infectious and immunological diseases [53]. Both solution and solid-phase routes were employed with hydroxamic acid functionality being incorporated via a separate coupling procedure.…”
With the emergence of combinatorial chemistry and high-speed parallel synthesis for drug discovery applications, the multicomponent reaction (MCR) has seen a resurgence of interest. Easily automated one-pot reactions, such as the Ugi [1] and Biginelli [2] reactions, are powerful tools for producing diverse arrays of compounds, often in one step and high yield. This review details the utility of MCRs in the drug discovery process and representative examples will be given demonstrating the successful impact of these reactions at different stages of the lead discovery, lead optimization and pre-clinical process development arenas. This will include applications spanning biological tools, traditional small molecules and ''biotech'' therapeutics respectively. Mechanistic details of these reactions are beyond the scope of the chapter and are described elsewhere in the book. The chapter will be organized chronologically around reaction classes, with subsections dealing with their impact on drug discovery. Representative case studies of the discovery of novel ligands spanning GPCR, protease, kinase and other gene-family classes will demonstrate the biological versatility of MCR derived small molecule-based ligands.
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