Bifeprunox (

INN Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...

) (code name DU-127,090) is an

atypical antipsychotic The atypical antipsychotics (AAP), also known as second generation antipsychotics (SGAs) and serotonin–dopamine antagonists (SDAs), are a group of antipsychotic drugs (antipsychotic drugs in general are also known as major tranquilizers and ne ...

which, similarly to

aripiprazole Aripiprazole, sold under the brand names Abilify and Aristada among others, is an atypical antipsychotic. It is primarily used in the treatment of schizophrenia and bipolar disorder. Other uses include as an add-on treatment in major depressiv ...

, combines minimal D₂ receptor

agonism Agonism (from Greek ἀγών ''agon'', "struggle") is a political and social theory that emphasizes the potentially positive aspects of certain forms of conflict. It accepts a permanent place for such conflict in the political sphere, but seeks ...

with

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory ne ...

agonism. It was under development for the treatment of

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

but has since been abandoned.Pipeline update - following an interim analysis the studies with bifeprunox for the treatment of schizophrenia is discontinued
Lundbeck Press Release. Bifeprunox has a novel mechanism of action. Conventional antipsychotics are classed into typical and atypical. The

typical antipsychotics Typical antipsychotics (also known as major tranquilizers, and first generation antipsychotics) are a class of antipsychotic drugs first developed in the 1950s and used to treat psychosis (in particular, schizophrenia). Typical antipsychotics ma ...

, such as

chlorpromazine Chlorpromazine (CPZ), marketed under the brand names Thorazine and Largactil among others, is an antipsychotic medication. It is primarily used to treat psychotic disorders such as schizophrenia. Other uses include the treatment of bipolar di ...

and

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychosi ...

, are potent D₂

receptor antagonist A receptor antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. Antagonist drugs interfere in the natural operation of rece ...

s. The

s started with

clozapine Clozapine is a psychiatric medication and is the first atypical antipsychotic (also called second-generation antipsychotic). It is primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate respo ...

, these are classified as multireceptor interacting compounds, acting as an agonist towards 5-HT_1A and an antagonist towards D₂ receptors among other 5-HT and DA receptors. Bifeprunox and other novel atypical antipsychotics will instead of antagonizing D₂ receptors, will act as

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...

s, as well as partial agonists towards 5-HT_1A receptors. In a multi-center, placebo-controlled study, 20 mg of bifeprunox was found to be significantly more effective than placebo at reducing symptoms of schizophrenia, with a low incidence of side effects. An NDA for Bifeprunox was filed with the

U.S. Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

in January 2007. The FDA rejected the application in August 2007. In June 2009, Solvay and Lundbeck decided to cease development because "efficacy data did not support pursuing the existing development strategy of stabilisation of non-acute patients with schizophrenia."

Synthesis

A related structure is called Adoprazine. Improved Synthesis: Bifeprunox synth

The reaction of 3-bromobenzyl alcohol 5852-73-0with mesyl chloride gives 3-bromobenzyl methanesulfonate 2732-02-3(2). This is used to alkylate 7-piperazin-1-yl-3H-1,3-benzoxazol-2-one 05685-26-5(1) leading t
CID:28466745
(3). The additional benzene ring is added by Suzuki cross-coupling with phenylboronic acid, completing the synthesis of bifeprunox (4).

References

{{Piperazines 5-HT7 agonists Atypical antipsychotics Phenylpiperazines Carbamates Benzoxazoles Biphenyls

Synthesis

See also

References