Inhibition isoform selectivity

Kunze, K.L. and Trager, W.F. (1993) Isoform-selective mechanism-based inhibition of human cytochrome P450 1A2 by furafylline. Chemical Research in Toxicology, 6 (5), 649-656. 

Histone deacetylase (HDAC) are often divided into various classes, (I, II, and IV) which are Zn " dependent (Table 1). Please note this chapter does not discuss the class HI HDACs which are NAD dependent, Sir-2-like deacetylases. The importance of class or isoform selective inhibition over pan-HD AC inhibition is currently being explored for its clinical relevance and thus, we will not explore in detail. However, a few natural products do demonstrate this type of class and isozyme selective inhibition which we will discuss briefly. 

Flavonoids, especially flavones and flavonols, also directly bind to several CYP isoforms (lAl, 1A2, IBl, 3A4) involved in xenobiotics metabolism and inhibit enzyme activity. Structure-activity relationships show rather high isoform selectivities depending on the flavonoid substitution pattern and contrasted inhibition mechanisms. For instance, inhibition by flavonoids of 7-methoxyresorufin O-demethylation in microsomes enriched in CYP lAl and 1A2 reveals that galangin (3,5,7-trihydroxyflavone) is a mixed inhibitor of CYP 1A2 (.ST = 8 nM) and a five times less potent inhibitor of CYP 1A1. By contrast, 7-hydroxy flavone is a competitive inhibitor of CYP lAl (Aii = 15 nM) and a six times less potent inhibitor of CYP 1A2. In addition, fairly selective inhibition of CYP IBl (specifically detected in cancer cells) by some flavonoids has been reported. For example, 5,7-dihydroxy-4 -methoxyflavone inhibits IBl, 1 Al, and 1A2 with IC50 values of 7, 80, and 80 nM, respectively. ... 

Mefenamate inhibits both COX isoforms with some preference for COX-2 in a whole blood assay and for COX-1 in an enzyme preparation of recombinant human enzymes and in a cellular assay. The COX-1 preference in the cellular assay shows a time dependency as preincubation of the cells decreases the ratio of COX isoform selectivity from 0.03 to 0.005 (Lora et al., 1998). 

The superfamily of P450 cytochrome enzymes is one of the most sophisticated catalysts of drug biotransformation reactions. It represents up to 25% of the total microsomal proteins, and over 50 cytochromes P450 are expressed by human beings. Cytochromes P450 catalyze a ivide variety of oxidative and reductive reactions, and react with chemically diverse substrates. Despite the large amount of information on the functional role of these enzymes combined with the knowledge of their three-dimensional structure, elucidation of cytochrome inhibition, induction, isoform selectivity, rate and position of metabolism all still remain incomplete [6]. 

Hinspach M, Li H, Jamal J, Yang W, Huang H, Hah J-M, Gomez-Vidal JA, Litzinger EA, Silverman RB, Poulos TL. Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase. Nature Struct. Mol. Biol. 2004 11 54— 59. 

Phenyl-2-aminopyridines have been explored as potential nNOS inhibitors (52). These compounds have some selectivity for nNOS over eNOS. They point out that the nNOS active site appears to be less sterically hindered than the eNOS active site. When the side-chain in the compound below is quinoline, the ICgo values (joM) for NOS inhibition are 0.21 nNOS and 0.83 eNOS for the PhCOCHa side-chain, the values are 0.14 nNOS and 0.89 eNOS for the PhCHaCO side-chain the values are 0.14 nNOS and 0.69 eNOS for the PhCH2CH2 side-chain the values are 0.26 nNOS and 0.45 eNOS, demonstrating almost complete loss of isoform selectivity. For the iBu side-chain the values are 0.35 nNOS and 0.37 eNOS, demonstrating no isoform selectivity. For the... 

Inhibitors specific for PKC-p have a more favorable toxicity profile. In fact, in a study by Aiello et al. (52), the effect of VEGF on retinal vascular permeability appeared to be mediated predominantly by the p-isoform of PKC. There was >95% inhibition of VEGF-induced permeability after administration of a PKC p-isoform-selective inhibitor (50). Studies are currently being conducted with a new PKC-p inhibitor, known as ruboxistaurin mesylate. Thus far, based on animal... 

Nakajima, M., M. Suzuki, R. Yamaji, H. Takashina, N. Shimada, H. Yamazaki et al. (1999). Isoform selective inhibition and inactivation of human cytochrome P450s by methylenedioxy-phenyl compounds. Xenobiotica 29, 1191-1202. 

All of the NOS isoforms can be inhibited to a variable degree, with N -substituted L-arginine analogs, for example, l-NMMA. Some of the NOS inhibitors show some isoform selectivity for example, calmodulin-binding agents such as trifluoperazine do not inhibit the calmodulin-independent (iNOS) isoform. For reasons that are not entirely understood, some of the... 

Isoform-selective inhibition of the human UDP-glucuronosyltransferases 2B7 and 2B17... 

Recently, Ghadiri has reported modified cyclic tetrapeptides with alterations in the peptide backbone. It was proposed that the most hioactive conformation of apicidin contains a cis amide rotamer and this was probed by incorporating a triazole isostere for the amide. The 1,5-triazole 33 (Figure 4.13) showed decreased isoform selectivity compared to apicidin, more potently inhibiting HDAC6 and HDAC8 than the natural product. 

ICso = 23 tiM) in its inhibition profile. Nevertheless, the linear hydroxamic acid 67 from the same library had a similar activity against HDACS (IC50 = 29 nM) and an improved HDAC1/HDAC8 isoform selectivity. 

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