Tissue-selective inhibitor

T Matsuoka, S Miyakoshi, K Tanzawa, K Nakahara, M Hosobuchi, N Serizawa. Purification and characterization of cytochrome P-450sca from Streptomyces car-bophilus. ML-236B (compactin) induces a cytochrome-P450sca in Streptomyces carbophilus that hydroxylates ML-236 B to pravastatin sodium (CS-514), a tissue-selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Eur J Bio-chem 184 707-713, 1989. 

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

Serizawa N, Matsuoka T. A two component-type cytochrome P-450 monooxygenase system in a prokaryote that catalyzes hydroxyiation of ML-236B to pravastatin, a tissue-selective inhibitor of 3.hydroxy 3 methylgluiaryl coenzyme A reductase. Biochim Biophys Acta 1991 1084 35-40. 

Baumann KL, Butler DE, Deering CF, Mennen KE, Millar A, Nanninga TN, Pahner CW, Roth BD. The convergent synthesis of CI-981, an optically active, highly potent, tissue selective inhibitor of HMGCoA reductase. Tetrahedron Lett. 1992 33 2283 2284. 

ACC2 selective inhibitors exemplified by 16 (ACC1 IC50 > 30 gM, ACC2 IC50 38 nM) have also been reported and were shown to reduce malonyl CoA levels in muscle tissues of Sprague-Dawley rats [51]. Although ACC inhibitors have... 

C. R. Sirtori, Tissue Selectivity of Hydroxymethylglutaryl Coenzyme A (HMG CoA) Reductase Inhibitors , Pharmacol. Ther. 1993, 60, 431-459. 

Sildenafil is a selective inhibitor of cGMP-specific PD-5 and therefore inhibits the degradation of cGMP PD-5, the predominant type in the corpus cavernosum, also is present in other tissues (e.g., lungs, platelets, and eye). TTie selective inhibition of this enzyme facilitates the release of nitric oxide and smooth muscle relaxation of the corpus cavernosa. Sildenafil enhances erection by augmenting nitric oxide-mediated relaxation pathways. It has been suggested that sildenafil s mechanism of action is due to cross-talk between cGMP- and cAMP-dependent transduction pathways within the cavernous muscles. 

H. Kinemuchi, H. Sugimoto, T. Obata, N. Satoh, S. Ueda, Selective inhibitors of membrane-bound semicarbazide-sensitive anime oxidase activity in mammalian tissues, Neurotoxicology 25 (2004) 325-335. 

A number of 1-substituted 2(l//)-pyrazinone derivatives show antithrombotic activity as selective inhibitors of the tissue Factor Vila complex <2003BML23I9> and were examined as mast cell tryptase inhibitors <2004BML48I9>. As a curious effect, dihydropyrazines proved to show DNA strand-breakage activity <2005CPB1359>. 

Common technical approaches to plant proteomics investigations are the extraction and the purification of proteins from crude tissue (8) however, due to the presence of a number of proteases and a low protein charge, a protection against proteolysis is highly recommended by adding selected inhibitors. Then the removal of nonproteinaceous products is operated according to the nature of the plant tissue (see scheme on Figure 2). 

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