Wednesday, April 16, 2014

Consider the Cyclopentane.

            The cyclopentane carbocyclic ring system, while ubiquitous in Nature, is not usually considered a privileged core structure for the development of a drug candidate due, in part, to a perceived synthetic intractability of stereochemically complex target molecules. But, to the contrary, a recent miniperspective in the Journal of Medicinal Chemistry by R. D. Taylor and co-workers, focusing on key scaffold components found in drugs listed in the FDA Orange Book, highlights the cyclopentane as a frequently encountered ring system (see Figure below, box 18/50). Another very recent J. Med. Chem. manuscript describes the discovery and development of simeprevir, a cyclopentane-based NS3/4A protease inhibitor, recently approved for the treatment of chronic HCV infection in combination with pegylated interferon-alpha and ribavirin.

from: Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. J. Med. Chem. 2014, Articles ASAP.
            In this month’s issue of Current Organic Chemistry, we advance the argument that the cyclopentane motif has been utilized as an effective core scaffold for several highly successful medicinal chemistry programs and, thus, has provided an underappreciated yet significant value for biomedical research. Moreover, we have compiled an assortment of modern synthetic methods that offer a wealth of attractive and accessible technologies for the stereocontrolled construction of exceedingly complex cyclopentanoid chemotypes of natural and unnatural origin.
            In this Review article, we contend that cyclopentanes should be regarded as privileged scaffolds for drug discovery research and that expanded screening campaigns of novel cyclopentane-based small molecule libraries for therapeutically relevant biological properties will have a favorable impact on the development of the active pharmaceutical ingredients (APIs) of tomorrow. The Review should be of great interest to scientists who apply state of the art synthetic technologies to drug discovery research.

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