Compounds in Clinical Development

Serotonin related compounds devoted to sleep disorders mainly act via 5-HT2A receptors. Compounds in clinical development reported with this mechanism of action are Eplivanserin, Pimavanserin, Pruvanserin, Volinanserin and APD-125. 

BMS-275291 is the first compound in clinical development from this new generation of MMPIs. BMS-275291 is a sulfhydryl-based broad-spectrum MMP inhibitor that is rationally designed to be less active toward the sheddases. Its chemical structure is shown in Fig. 1. 

Compounds in clinical development for the treatment of patients with HBV infection include the nucleoside analogs emtricitabine, clevudine, valtorcitabine, pradefovir, and alamifovir, as well as the immunologic modulator thymosin alpha-1, agents that facilitate uptake by the liver using conjugation to ligands, and RNA interference compounds. 

The development of the new class of compounds known as 5a-reduc-tase inhibitors has significantly advanced our understanding of androgen biology. Finasteride, a selective inhibitor of the human type 2 5a-reductase enzyme, was the first of this class of compounds in clinical development, and extensive clinical trials have established its usefulness... 

A comprehensive website summarizing the status of tumor antiangiogenic compounds in various stages of clinical trial is maintained by the National Cancer Institute at www.cancer.gov/clinicaltrials/developments/ anti-angio-table. Following is a survey of the most important substances currently in clinical development. 

Several steroidal and non-steroidal glucocorticoid receptor selective dissociated agonists are in development by many pharmaceutical companies and some are now in clinical development. This suggests that the development of dissociated glucocorticoids with a greater margin of safety is possible and may even lead to the development of oral compounds that do not have significant adverse effects. 

Recently Turner and coworkers have sought to extend the deracemization method beyond a-amino acids to encompass chiral amines. Chiral amines are increasingly important building blocks for pharmaceutical compounds that are either in clinical development or currently licensed for use as drugs (Figure 5.7). At the outset of this work, it was known that type II monoamine oxidases were able to catalyze the oxidation of simple amines to imines in an analogous fashion to amino acid oxidases. However, monoamine oxidases generally possess narrow substrate specificity and moreover have been only documented to catalyze the oxidation of simple, nonchiral... 

In addition to the NRTI lamivudine (3TC) and the NtRTI adefovir dipivoxU and tenofovir disoproxil fumarate (which has been recently licensed for the treatment of chronic hepatitis B), two other nucleoside analogues, that is, entecavir and L-dT (tel-bivudine) (Fig.4aa), have been licensed for the treatment of HBV infections. Two other compounds 3 -Val-L-dC (valtorcitabine) and L-FMAU (clevudine) (Fig. 4aa) are in clinical development for the treatment of HBV infections, and yet two other compounds, that is, racivir and elvucitabine (Fig. 3), yield potential for the treatment of both HBV and HIV infections. 

The dimethylheptyl side-chain analogue of 9-carboxy-A -THC, ajulemic acid, CT-3, (166) is currently in clinical development for treatment of pain and inflammation [121, 122]. Compound (166) does show some affinity for CBi and CB2 receptors, but may also exert anti-inflammatory and analgesic effects through other mechanisms. It does not appear to be psychoactive in humans [123]. 

Recent analyses demonstrating comparable mean values of lipophilicity, H-bond donors, and polar surface area between older (pre-1983) and newer (1983-2002) oral drugs suggest that these physicochemical attributes are fundamental characteristics of successful drugs. The noted increasing lipophilicity of compounds entering clinical development in recent years may have contributed to a commensurate higher rate of attrition [5,6]. 

Both plate reader and mass spectrometry based methods are commonly used for screening. The selection of a technique depends on instrument availability, throughput needs and the stage of compound advancement. For the characterization of compounds in drug development and clinical candidates, assays carried out using drug-like probes and analyzed by LC-MS/MS methods are considered the gold standard [117]. 

Components of F-[IV entry and targets for entry inhibition including coreceptor blockers. There are many different stages of viral entry and each of these is specifically susceptible to antagonism by specific compounds. The compounds listed above are in clinical development with the exception of enfuvirtide, which was approved by the Food and Drug Administration (FDA). (Reprinted with permission from Dr. Robert W. Dorns. Available at http //cHnicaloptions.com. Accessed August 25, 2005.)... 

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