Peptidomimetics clinical trials

Vertex also put in clinical trial VX-765, another caspase-1 -specific, YVAD-derived peptidomimetic that is in vitro slightly more potent then pralnacasan (IC50 0.8 nM). Evaluation of VX-765 in a mouse model of oxazolone-induced dermatitis showed a dose-dependent (10-100 mg/kg) inhibition of ear inflammation. Consequently, VX-765 was enrolled in a 4-week phase Ila safety and pharmacokinetic study for psoriasis. However, Vertex has not communicated any results yet. 

Several other inhibitors of nonreceptor PTKs are currently in development but only a few of them are studied in clinical trials. Noteworthy, Dasatinib does not only inhibit c-Abl, but also potently blocks Src activity, a property that may contribute to its beneficial clinical effects in CML. Other kinase inhibitors being developed that inhibit c-Abl and/or Src are AZD-0530, AP-23994, PD-0183805, SU-6656, and Bosutinib (SKI-606). Furthermore, peptidomimetic SH2 domain inhibitors for Src, such as AP-22408 have been designed that decrease bone resorption and may be promising drugs to treat osteoporosis and other bone diseases, such as Paget s disease and osteolytic bone metastasis. 

Direct thrombin inhibitors such as hirudin, Hirulog, the peptide aldehyde efegatran, and peptidomimetic compound argatroban have undergone clinical trials. Their application in the prevention and treatment of deep vein thrombosis contin-... 

IDUN Pharmaceuticals (San Diego, CA) also reported development of a potent peptidomimetic irreversible oxamyl dipeptide inhibitor lDN-6556 that uses 2,3,5,6-tetrafluro-phenoxymethylketone warhead (Fig. 2f) (37, 38). This molecule preferentially accumulates in the liver, which results in pronounced liver protection in animal models [for example, after Fas-induced liver injury (39)], and showed significant promise in clinical trials of acute alcoholic hepatitis, human liver preservation injury, and chronic hepatitis C (38, 40, 41). 

Recently (1996) the FDA (U.S.) has given fast track approval to three peptidomimetic HIV-protease inhibitors. These agents were released based on fewer and shorter clinical trials than would be required if the urgency of AIDS were not so acute. As a result, drug interactions and adverse effects are not fully known at this time. 

A large number of peptidomimetics are currently entering clinical trials, typically protease inhibitors and anti-cancer agents, which emphasizes the importance of developing reactions which efficiently modify peptides or peptide-like structures to increase their drug-like properties. Azides are important dipoles in 1,3-dipolar cycloaddition reactions and react with dipolarophiles such as alkynes and nitriles, to afford [l,2,3]-triazoles and tetrazoles, respectively. 

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