Basimglurant

Basimglurant (INN; developmental code RG-7090 and RO-4917523) is a negative allosteric modulator of the mGlu₅ receptor which is under development by Roche and Chugai Pharmaceutical for the treatment of treatment-resistant depression (as an adjunct) and fragile X syndrome.^[1][2] As of November 2016, it has undergone phase II clinical trials for both of these indications.^[3]

Basimglurant

Clinical data
Routes of administration	By mouth
ATC code	none
Legal status
Legal status	Investigational
Identifiers
IUPAC name 2-chloro-4-{[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl]ethynyl}pyridine
CAS Number	802906-73-6
PubChem CID	11438771
IUPHAR/BPS	9309
DrugBank	DB11833
ChemSpider	9613635
UNII	3110E3AO8S
KEGG	D10864
ChEMBL	ChEMBL3301626
CompTox Dashboard (EPA)	DTXSID801025734
Chemical and physical data
Formula	C18H13ClFN3
Molar mass	325.77 g·mol−1
3D model (JSmol)	Interactive image
SMILES Clc3nccc(C#Cc2nc(n(c1ccc(F)cc1)c2C)C)c3
InChI InChI=1S/C18H13ClFN3/c1-12-17(8-3-14-9-10-21-18(19)11-14)22-13(2)23(12)16-6-4-15(20)5-7-16/h4-7,9-11H,1-2H3 Key:UPZWINBEAHDTLA-UHFFFAOYSA-N

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.^[4] In partnership with Chugai Pharmaceutical, basimglurant is currently still undergoing revision from previous drug trials as of November 2016.^[3]

Pharmacology

Mechanism of action

Preclinical research trials found that basimglurant has a high specificity for the glutamate receptor mGlu₅, and as a consequence of this specificity, also has a high level of safety.^[4]

Pharmacokinetics

Preclinical drug trials showed that basimglurant possessed a terminal half-life of 7 hours in rats and 20 hours in monkeys, indicating a dosing regimen of once daily in possible human patients.^[4] Research with rats and monkeys revealed a bioavailability of 50%, with additional studies showing that basimglurant has a rate of plasma protein binding of 98 to 99%.^[4]

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 cohort, and a placebo 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.^[5]

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.^[1][2][6]

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, it will most likely undergo future iterations and attempt to pass drug trials again.

History

Basimglurant was originally developed for the treatment of fragile X syndrome,^[7] 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.

See also

• List of investigational antidepressants