Basimglurant

Last updated
Basimglurant
Basimglurant.svg
Clinical data
Routes of
administration 		By mouth
ATC code
  • none
Legal status
Legal status
  • Investigational
Identifiers
  • 2-chloro-4-{[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-yl]ethynyl}pyridine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C18H13ClFN3
Molar mass 325.77 g·mol−1
3D model (JSmol)
  • Clc3nccc(C#Cc2nc(n(c1ccc(F)cc1)c2C)C)c3
  • 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]

Contents

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

References

  1. 1 2 "Roche - Pipeline". 2014. Retrieved 2014-08-01.
  2. 1 2 "Roche Group Development Pipeline" (PDF). 2014. Archived from the original (PDF) on 2014-08-08. Retrieved 2014-08-01.
  3. 1 2 "Basimglurant". Adis Insight. Springer Nature Switzerland AG. Retrieved 2016-11-20.
  4. 1 2 3 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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