Basimglurant

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;

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]

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.

References

^ ^a ^b "Roche - Pipeline". 2014. Retrieved 2014-08-01.
^ ^a ^b "Roche Group Development Pipeline" (PDF). 2014. Archived from the original (PDF) on 2014-08-08. Retrieved 2014-08-01.
^ ^a ^b "Basimglurant". Adis Insight. Springer Nature Switzerland AG. Retrieved 2016-11-20.
^ ^a ^b ^c ^d Lindemann L, Porter RH, Scharf SH, Kuennecke B, Bruns A, von Kienlin M, et al. (April 2015). "Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression". The Journal of Pharmacology and Experimental Therapeutics. 353 (1): 213–33. doi:10.1124/jpet.114.222463. PMID 25665805.
^ Clinical trial number NCT02433093 for "A Study of the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Dose Basimglurant in Healthy Subjects and in Patients With Major Depressive Disorder (MDD)" at ClinicalTrials.gov
^ Quiroz JA, Tamburri P, Deptula D, Banken L, Beyer U, Rabbia M, et al. (July 2016). "Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial". JAMA Psychiatry. 73 (7): 675–84. doi:10.1001/jamapsychiatry.2016.0838. PMID 27304433.
^ "Roche abandons another Fragile X R&D program after PhII trials flunk out | FierceBiotech". www.fiercebiotech.com. 10 September 2014. Retrieved 2016-11-20.

[Roche2014a-1] "Roche - Pipeline". 2014. Retrieved 2014-08-01.

[Roche2014b-2] "Roche Group Development Pipeline" (PDF). 2014. Archived from the original (PDF) on 2014-08-08. Retrieved 2014-08-01.

[Adis_Insight_Basimglurant-3] "Basimglurant". Adis Insight. Springer Nature Switzerland AG. Retrieved 2016-11-20.

[Lindemann_2015-4] Lindemann L, Porter RH, Scharf SH, Kuennecke B, Bruns A, von Kienlin M, et al. (April 2015). "Pharmacology of basimglurant (RO4917523, RG7090), a unique metabotropic glutamate receptor 5 negative allosteric modulator in clinical development for depression". The Journal of Pharmacology and Experimental Therapeutics. 353 (1): 213–33. doi:10.1124/jpet.114.222463. PMID 25665805.

[5] Clinical trial number NCT02433093 for "A Study of the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Dose Basimglurant in Healthy Subjects and in Patients With Major Depressive Disorder (MDD)" at ClinicalTrials.gov

[6] Quiroz JA, Tamburri P, Deptula D, Banken L, Beyer U, Rabbia M, et al. (July 2016). "Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression: A Randomized Clinical Trial". JAMA Psychiatry. 73 (7): 675–84. doi:10.1001/jamapsychiatry.2016.0838. PMID 27304433.

[7] "Roche abandons another Fragile X R&D program after PhII trials flunk out | FierceBiotech". www.fiercebiotech.com. 10 September 2014. Retrieved 2016-11-20.

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