Tamoxifen discovery

One first needs to stress that risk-taking is inherent to pharmaceutical discovery and therefore one often need to take conscious risks when one selects a development candidate. Although challenging compounds have been successfully developed (with massive investments in technical R D) in the past (cyclosporine, tamoxifen, amiodarone. .. ), the question is how many of these difficult compounds one can afford in a drug development pipeline For one successful compound, how many did fail despite significant (or sometimes desperate) efforts From our experience in the past few years a few points emerge ... 

Jordan, V.C. (2003) Tamoxifen a most unlikely pioneering medicine. Nature Reviews Drug Discovery, 2, 205-213. 

Tamoxifen Variants The earliest triphenylethylene identified as an ER modulator is clomiphene (Clomid ) and was identified by Merrell in 1958. The compound was intended to be used as a contraceptive, based on its contraceptive activity in rat. However, it behaved exactly the opposite in woman, inducing ovulation and improving subfertility. The compound was therefore marketed as a therapy for infertility. The commercial preparation consists of a mixture of enclomiphene and zuclomi-phene, the latter acting as an agonist. Yet, even 50 years after it discovery, clomiphene... 

As mentioned in the introduction, metallocene-type complexes based on the early transition metals were evaluated as anticancer compounds shortly after the discovery of cisplatin. While the biological activity of each of the metallocene dihalides is unique, titanocene dichloride 7 has been the subject of a number of studies and even entered clinical evaluation, although evaluation was discontinued (not due to its anti-proliferative properties), principally due to formulation problems, despite showing superior activity to certain cancers than other established drugs. This class of compound continues to be modified and studied for anticancer activity, for example, the titanocene-type derivative of tamoxifen 1, described above, and other developments described below. 

This family of receptors expressed, as their name suggests, within the cell are already the targets for many drug discovery programs. For example, tamoxifen is widely used for the treatment of breast cancer and is an antagonist of the estrogen receptor. Many synthetic analogs of corticosteroids are used in asthma treatment. The... 

The set of plans for the anticancer agent tamoxifen show a nice contrast between the original discovery route by Imperial Chemical Industries (ICI) [122,123], which uses classical chemistry versus modem routes that employ cross coupling chemistry mediated by palladium salt... 

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