Basimglurant (

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 ...

) (developmental code names RG-7090, RO-4917523) is a

negative allosteric modulator In pharmacology and biochemistry, allosteric modulators are a group of substances that bind to a receptor to change that receptor's response to stimulus. Some of them, like benzodiazepines, are drugs. The site that an allosteric modulator binds t ...

of the mGlu₅ receptor which is under development by

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

and Chugai Pharmaceutical for the treatment of

treatment-resistant depression Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...

(as an adjunct) and fragile X syndrome. As of November 2016, it has undergone phase II

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, diet ...

s for both of these indications. It was discovered in a medicinal chemistry effort conducted at Roche starting from the results of a small molecular weight compound library high-throughput screen based on a Ca21 mobilization assay with human mGlu5a (Jaeschke et al., 2015). The high-throughput screen identified several mGlu5 antagonists such as MPEP, MTEP, and fenobam. In partnership with Chugai Pharmaceutical, basimglurant is currently still undergoing revision from previous drug trials as of November 2016.

Pharmacology

Mechanism of action

Preclinical research trials found that basimglurant has a high specificity for the

glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system ...

mGlu₅, and as a consequence of this specificity, also has a high level of safety.

Pharmacokinetics

Preclinical drug trials showed that basimglurant possessed a

terminal half-life Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

of 7 hours in rats and 20 hours in monkeys, indicating a dosing regimen of once daily in possible human patients. Research with rats and monkeys revealed a

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of 50%, with additional studies showing that basimglurant has a rate of

plasma protein binding Plasma protein binding refers to the degree to which medications attach to proteins within the blood. A drug's efficiency may be affected by the degree to which it binds. The less bound a drug is, the more efficiently it can traverse or diffuse t ...

of 98 to 99%.

Clinical trials

Phase I clinical trials for basimglurant began in April 2015, and finished in September 2015. 56 people were spread out among 4 healthy cohorts, a

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

cohort, and a

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. In general, placebos can af ...

cohort. The trial was undertaken to study (and verify) the safety of basimglurant as a potential drug. Completion of this trial allowed for basimglurant to begin phase II drug trials. Phase II clinical trials have been undertaken, and a lack of efficacy was found overall. Improved secondary endpoints though of 1.5 mg dosage has prompted future clinical trials of the drug.

Future

Basimglurant has shown the desired characteristics of a drug with high bioavailability, few safety liabilities, and promise in the secondary endpoints of a phase IIb trial. Basimglurant will most likely undergo future iterations and attempt to pass drug trials again due to the large investment already poured into the drug to develop it this far.

History

Basimglurant was originally developed for the treatment of fragile X syndrome, but after failing phase II clinical trials Roche abandoned the drug in this field of application and is renewing basimglurant as part of a treatment for depression.

References

{{Metabotropic glutamate receptor modulators Antidepressants MGlu5 receptor antagonists Organochlorides Fluoroarenes Pyridines Alkyne derivatives