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Numerous variations on structural motifs exist within pharmaceutical compounds that have entered the clinic. These variations have amounted over many decades based on years of drug development associated with screening natural products and de novo synthetic systems. Caged (or bridged) bicyclic structural elements offer a variety of diverse features, encompassing three-dimensional shape, and assorted pharmacokinetic properties. This review highlights approximately 20 all carbon cage containing pharmaceuticals, ranging in structure from bicyclo[2.2.1] through to adamantane, including some in the top-selling pharmaceutical bracket. Although, a wide variety of human diseases, illnesses and conditions are treated with drugs containing the bicyclic motif, a common feature is that many of these lipophilic systems display CNS and/or neurological activity. In addition, to an extensive overview of the history and biology associated with each drug, a survey of synthetic methods used to construct these entities is presented. An analysis section compares natural products to synthetics in drug discovery, and entertains the classical caged hydrocarbon systems potentially missing from the clinic. Lastly, this unprecedented review is highly pertinent at a time when big pharma is desperately trying to escape flatland drugs. |
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