Lurasidone is FDA approved for the treatment of schizophrenia and depressive episodes associated with bipolar I disorder. It has not yet received regulatory approval in Australia or the UK. It received EMA approval on January 24, 2014. It was launched in Canada for the treatment of schizophrenia in September 2012, Health Canada giving their Summary Basis of Decision (SBD) as favourable on October 15, 2012. Switzerland is the first and only European country so far where lurasidone is approved for schizophrenia.
In July 2013 lurasidone received approval for bipolar I depression. Few available atypical antipsychotics are known to possess antidepressant efficacy in bipolar disorder (with the notable exceptions being quetiapine,olanzapine and maybeasenapine) as a monotherapy, even though the majority of atypical antipsychotics are known to possess significant antimanic activity, which is yet to be clearly demonstrated for lurasidone.
As with other atypical neuroleptics, lurasidone should be used with caution in the elderly because it puts them at an increased risk for a stroke or transient ischemic attack; however, these risks are not likely to be greater than those associated with antipsychotics of other classes.
Lurasidone is metabolized in the liver via the enzymeCYP3A4. This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole or grapefruit juice, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin or St. John's wort can reduce plasma levels and consequently decrease the effects of the drug.
The large scale synthesis of lurasidone began with the bis-mesylation of commercially available diol 1 to furnish disulfone 2. Dialkylation of piperazine3 with disulfone 2 under basic conditions afforded spirocyclic tetralkyl ammonium species 4. By subjecting tetralkyl ammonium salt 4 to basic conditions in the presence of succinimide5 an interesting regioselective ring-opening alkylation reaction occurs to form the 1,2-trans-substituted cyclohexane motif of lurasidone. Finally, exposure of lurasidone to hydrochloric acid provided the lurasidone hydrochloride salt.
Synthetic Route to Lurasidone Hydrochloride
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