A Promising Clinical Candidate

In terms of chemical strucmre, garenoxacin contains an isoindoline moiety at C7 via a sp C-sp C bond, unlike most quinolones, which have a sp C-N bond. This brief section will only discuss the incorporation of the C7 side-chain (Hayashi et al., 2002) and not the 

TABLE 4.6. MICgo of GAR Compared with Other Quinolones Against Gram-Positive and Gram-Negative Bacteria 

Andriole, V. T. (Ed.) (2000a). The Quinolones, Academic Press, San Diego. 

Andriole, V. T. (2000b). In The Quinolones, Andriole, V. T. (Ed.) Academic Press, San Diego, p. 3. Andriole, V. T. (2003). In Antibiotic and Chemotherapy Antiinfective Agents and their Use in Therapy, Pinch, R. G. et al. (Eds) Churchill Livingstone, Edinburgh, (29) 349-373. 

Bryskier, A. (2005). In Antimicrobial Agents Antibacterials and Antifungals, Bryskier, A. (Ed.) 

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Ramoplanin is a promising clinical candidate for treatment of infectious diseases caused by gram-positive bacterial, and is now under clinical study. 

This analogue of y-aminobutyric acid GABA (322) appears to be a promising clinical candidate as an antiepileptic drug. 

Natural products have been identified as the active principle of herbs and extracts used in folk medicine [1], The importance of natural products in the pharmaceutical industry has continued to the present day and is reflected by the fact that close to half of the best selling pharmaceuticals are either natural products (e.g. cyclosporine, Taxol, FK 506) or derivatives thereof [3]. In high throughput screening processes performed by the pharmaceutical industry natural product extracts exhibit a hit rate which is estimated to be substantially higher than the hit rate of random libraries from combinatorial chemistry. Natural products such as epothilones, discodermolide or ecteinascidin are promising clinical candidates for future cancer treatment. 

Chapter 4 tells of a successful program in which potent non-peptide inhibitors of HIV protease from the AIDS virus were developed. Cou-marins and dihydropyranones were identified as viable chemical leads via screening. Rational drug design, aided by molecular modeling and X-ray crystal analysis, along with the development of sound structure-activity relationships, yielded a number of promising clinical candidates. 

Because of the immense abuse potential with amphetamine and particularly meth amphetamine, the vigorous and intensive search is already on to suggest better and safer alternative medical treatments for the CNS stimulants to combat such critical disorders efficiently. Modafinil, after recent clinical trials, may prove to be a promising alternative candidate drug in treating narcolepsy. ... 

Figure 2.4 Simplified model of drug discovery startup development. Succeed and Fail first refer to the ability to attract a corporate partner, then later to the production of a promising drug candidate in clinical trials.

The majority of promising drug candidates emerging from marine natural products research to date are potential cancer treatments. Six anti-cancer compounds that are either marine natural products or synthetic analogs of marine natural products have made it to clinical trials. The first of these compounds to enter clinical trials was didemnin B (43), one of a family of cyclic depsipetides isolated from the Caribbean tunicate Trididemnum solidum Didemnin B was advanced to Phase II clinical trials for treatment of small cell lung cancer, myeloma, prostate cancer, and melanoma. Unfortunately, no favorable responses were found so the compound has been withdrawn. Crude extracts of another Caribbean tunicate, Ecteinascidia turbinata, showed extremely... 

Following the synthesis of the sodium, potassium, and succinic acid esters of CA-4, which were not soluble in water [35], CA-4P (9), the disodium phosphate pro-drug was developed and is currently in phase II of clinical trials [36]. CA-4P is a promising candidate for combination anti-cancer therapy because it is inactive as a phosphate but is rapidly hydrolyzed in vivo to the active CA-4, 7 compound [31,37]. 

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