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| Formula | C17H19FN4S |
| Molar mass | 330.43 g·mol−1 |
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Flumezapine is an abandoned, investigationalantipsychotic drug that was studied for the treatment of schizophrenia. Flumezapine failedclinical trials due to concern for liver and muscle toxicity. Flumezapine is structurally related to the common antipsychoticolanzapine—a point that was used against its manufacturer,Eli Lilly and Company, in a lawsuit in which generic manufacturers sought to void the patent on brand name olanzapine (Zyprexa). Although flumezapine does not differ greatly from olanzapine in terms of its structure, the difference was considered to be non-obvious, and Eli Lilly's patent rights on Zyprexa were upheld.
Flumezapine was studied for the treatment ofschizophrenia.[1]
In the clinical trial that lead to the cessation of its development as a drug, flumezapine was noted to be toxic. The administration of flumezapine led to the adverse effects of elevating the plasma concentration ofcreatine phosphokinase (CPK) and the liver enzymesaspartate transaminase (AST) andalanine transaminase (ALT).[1] These liver enzyme elevation risks are similar to that of the neuroleptic drugchlorpromazine.[1] Flumezapine also inducedextrapyramidal symptoms (EPS) in patients during early clinical trials.[1]
Flumezapine is classified as asecond-generation antipsychotic, which includes other drugs such asclozapine.[2]
Flumezapine is an antipsychotic, due to its antagonism ofdopamine receptors in the brain. However, like other antipsychotics, it also antagonizes other receptors in the brain, such as themuscarinic receptors. In comparison toclozapine, another antipsychotic, flumezapine's antidopaminergic toanticholinergic ratio is 5 times higher, indicating higher dopamine receptor blockade with less anticholingergic properties.[3]
Flumezapine is a thioeno[2,3-b][1,5]benzodiazepine akin toolanzapine, differing only by the substitution of afluorine atom (F) for ahydrogen atom (H) on thephenyl ring.[4] The fluorine atom acts as anelectron-withdrawing substituent; this was the same rationale given in the patent information for the electron-withdrawingchlorine atom on the antipsychoticclozapine.[5]
Developed alongside olanzapine byEli Lilly and Company, the clinical development of flumezapine was halted due to toxicology concerns.[6] Its research designation was LY-120363.[7] The other analogues studied, (1) substituting flumezapine's methyl group for an ethyl group (ethyl flumezapine)[8] and (2) substituting flumezapine's methyl group for an ethyl group and its fluorine atom for a hydrogen atom, also failed due to concerns ofgranulocyte suppression andelevated cholesterol duringin vivo studies on dogs, respectively.[9]
In 2005, flumezapine was at the heart of a lawsuit filed by drug manufacturer Eli Lilly against three generic drug manufacturers (Zenith Goldline Pharmaceuticals,Dr. Reddy's Laboratories, andTeva Pharmaceuticals) that sought to develop generic versions ofZyprexa (olanzapine).[10] The generic companies claimed the Eli Lilly's patent on olanzapine was null and void due to the expiration of the similar compound, flumezapine, from which the discovery of olanzapine would be inevitable.[10] In the judge's ruling, theU.S. District Court for the Southern District of Indiana sided with Eli Lilly by upholding Eli Lilly's patent (Patent No. 5,229,382), finding that the substitution of a fluorine atom for a hydrogen atom in olanzapine was a non-obvious difference between the two compounds, which deserved continued patent protection.[10][11] As Nicole L. M. Valtz writes in her commentary on the case,
"Mere identification in the prior art of each component of a composition does not render the combination obvious; the law requires some motivation to select and combine the references to reach the claimed invention."[12]
Theselection patent was also upheld in Canada.[13]The patent for Zyprexa expired in 2011.[10]
