Inhibitors target selection

De Clercq E (1993) HlV-l-spedfic RT inhibitors highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. Med Res Rev 13 229-258... 

SB-366791 (18) emerged from screening an in-house library as a potent competitive inhibitor of both hTRPVl and rTRPVl, endowed with superior target selectivity compared to capsazepine [84]. Structure-activity relationships of SB-366791 remain to be reported. 

Significant work continues by both the academic groups and the pharmaceutical industry to validate the FASH targets and discover relevant inhibitors. A selection of some efforts to inhibit bacterial fatty acid biosynthesis at various stages is presented in this chapter. 

There are a variety of structural classes of compounds that are active against each phosphodiesterase, and evidence suggests that selective inhibitors of PDEs can be identified. The structural diversity of PDE inhibitors provides a multitude of opportunities for development of compounds with drug-like properties. Furthermore, phosphodiesterase inhibition, which avoids direct interaction of a compound with a cell surface or nuclear receptor, may circumvent some of the target selectivity issues that can complicate receptor-based therapeutic approaches. As noted above, the specific subcellular distribution of phosphodiesterase enzymes is a key feature of their ability to modulate intracellular signaling pathways. This localization of the enzyme may minimize non-specific target... 

Unlike the previously discussed compounds, which inhibit MTP in both liver and intestine, an intestine-selective orally-active MTP inhibitor JTT-130 (structure not yet disclosed) has been reported to decrease plasma cholesterol and TG in guinea pigs with no hepatic lipid accumulation [16]. Although further studies in human are needed, inhibitors that selectively target intestinal MTP might be a safer alternative as a treatment for hyperlipidemia than the liver-targeting MTP inhibitors. 

Overall, trifluorophenyl analogue 1 was superior to all triazolopiperazine derivatives with respect to DPP-4 potency, off-target selectivity, pharmacokinetic profile and in vivo efficacy in preclinical species and was selected for further development. In vitro potency and selectivity of compound 1 (sitagliptin) are illustrated in Table 17.8. Sitagliptin is a very selective D P P-4 inhibitor, showing 2700-fold selectivity over D P P-8 and more than 5000-fold selectivity over other DASH proteins. Sitagliptin was further profiled in an extensive panel of over 170 enzymes, receptors and ion... 

Buchanan SG. Protein structure discovering selective protein kinase inhibitors. TARGETS 2003 2 101-8. 

Selective Inhibitors Targeting Individual ErbB Family Members. 96... 

The 1990s witnessed an intensive effort to develop small-molecule inhibitors of FTase, which eventually provided proof of concept for this target in preclinical models. Although the original hypothesis envisioned inhibitors that selectively depleted farnesylated Ras proteins from tumor cell membranes, the emerging data on FTIs indicated mechanisms which were subtle and more complex (for a review, see [13]). 

Reverse Genetics baC Broad search for phenotype associated with perturbations of specific genes New role for target Select target Find specific inhibitor Broadly assay for phenotypes... 

Chemo- genomics BaC Use information on targets to identify specific modulators, then look for phenotypes Compounds/drugs for novel targets Select targets Identify inhibitor Broadly assay for phenotypes... 

The 6-acrylamido-4-anilinoquinazolines constitute another class of irreversible inhibitor targeted at the EG Fr tyrosine kinase. This type of inhibitor has been derived from the very potent (6 pM) and selective 4-anilinoquinazolines, e.g., PD-0153035 [4e], A detailed description of the binding mode of the 4-anilinoquinazolines is given in Section 7.4.1. The Michael acceptor at the 6-position of the 4-anilino-... 

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