Inhibitor design, phosphodiesterases

Some other hydrolytic enzymes, in addition to proteases, that are important drug targets include protein phophatases, phosphodiesterases, nucleoside hydrolases, acetylhydolases, glycosylases, and phospholipases. Structure-based inhibitor design is currently being applied to a number of these enzymes. The last three mentioned have been successfully tar-... 

Krier M, de Araujo-Junior JX, Schmitt M, Duranton J, Justiano-Basaran H, Lugnier C, Bourguignon JJ, Rognan D. Design of small-sized libraries by combinatorial assembly of linkers and functional groups to a given scaffold application to the structure-based optimization of a phosphodiesterase 4 inhibitor. J Med Chem 2005 48 3816-22. 

The most X-ray intensive screening method was described by Card et al. [8] on the design of phosphodiesterase (PDE) inhibitors (Figure 1.7). The authors initially biochemically screened a 20,000 member library of small molecular weight (120-350 MW) core scaffold compounds against 5-PDE isoforms at 200 pM. Multiple isoforms of PDE were used in order to eliminate the number of false positives obtained from the screen. There were 316... 

A recent report from the U. K. deals with 1,4-bis(oxodihydropyridazin-yl)benzenes and congeners which are also potent phosphodiesterase inhibitors and inodilators [159], This investigation, together with computer-aided modelling studies on various phosphodiesterase III inhibitors [160], may well stimulate the rational design of additional pyridazine-derived inodilators. 

A more recent example is that of sildenafil which, as a result of observations made during Phase I studies in male volunteers, is now used to treat erectile dysfunction. Sildefanil had originally been designed as an analogue of zaprinast, and a more selective phosphodiesterase inhibitor (PDE5) for use as a cardiovascular agent (see Chapter 1-1). 

Beavo, J.A. and Reifsnyder, D.H. (1990). Primary sequence of cychc nucleotide phosphodiesterase isozymes and the design of selective inhibitors. TiPS 11,150 155. 

Figure 6.22 An initial hit and two of its optimized analogs. (Card, G.L. et al. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat. Biotechnol. 2005, 23, 201-207.)...

Synthesis and designing aspects of coumarin derivatives as monoamine conformation-specific effects of Raf kinase inhibitors 12JMC7332. Current landscape of phosphodiesterase lOA (PDEIOA) inhibition 12JMC7299. 

Ochiai K, Takita S, Eiraku T, Kojima A, Iwase K, Kishi T, Fukuchi K, Yasue T, Adams DR, Allcock RW, Jiang Z, Kohno Y (2012) Phosphodiesterase inhibitors. Part 3 design, synthesis and structure-activity relationships of dual PDE3/4-inhibitory fused bicycUc heteroaromatic-dihydropyridazinones with anti-inflammatory and bronchodUatory activity. Bioorg Med Chem 20 1644-1658... 

Raboisson P, Lugnier C, Muller C, Reimund JM, Schultz D, Pinna G, Le Bee A, Basaran H, Desaubry L, Gaudiot F, Seloum M, Bourguignon J (2003) Design, synthesis and structure-activity relationships of a series of 9-substituted adenine derivatives as selective phosphodiesterase type-4 inhibitors. Eur J Med Chem 38 199-214... 

Dimethylimidazo[l,5-a]quinoxalines 189, containing different substituents in the 1-, 6- and 8-positions, and above-mentioned imidazo[l,5-a]quinoxalines 188 are lOA phosphodiesterase (PDEIOA) inhibitors and can be used for designing antischizophrenia drugs (Malamas et al. 2010, 2011b). 

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