Basimglurant
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| Clinical data | |
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| ATC code | none |
| Identifiers | |
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| CAS Number | 802906-73-6 |
| PubChem (CID) | 11438771 |
| ChemSpider | 9613635 |
| Chemical and physical data | |
| Formula | C18H13ClFN3 |
| Molar mass | 325.767 g/mol |
| 3D model (Jmol) | Interactive image |
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Basimglurant (RO4917523, RG7090; C18H13ClFN3, mol. wt. 325.77) was discovered in a medicinal chemistry effort conducted at F. Hoffmann-La Roche AG 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.[1] In combination with Chugai Pharmaceutical, Basimglurant is currently still undergoing revision from previous drug trials as of November 2016.[2]
Pharmacological Mechanism
Basimglurant (INN) (code names RG-7090, RO4917523) 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.[3][4]
Pharmacokinetics
Pre-clinical drug trials showed that Basimglurant possessed a half life of 7 hours in rats and 20 hours in monkeys, indicating a dosing regimen of once daily in possible human patients.[1]
Bio-availability, Efficacy, and Safety
- Pre-clinical research trials revealed that Basimglurant has a high specificity for the mGlu5 receptor, and as a consequence of this specificity also has a high level of safety.[5]
- Pre-clinical trials of rats and monkeys revealed a bio-availability of 50%, with additional studies showing Basimglurant has the same binding affinity as other anti-depressive drugs (98-99%) [1]
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 MDD 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.[6]
As of November 2016, it went through phase II clinical trials for both of these indications, and a lack of efficacy was found overall. Improved secondary endpoints though of 1.5 mg dosage though has prompted future clinical trials of the drug.[3][4][7]
History
Basimglurant was originally meant for the treatment of Fragile X Syndrome,[8] 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.
Future
Basimglurant has shown the desired characteristics of a drug with high bio-availability, 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.
See also
References
- 1 2 3 Lindemann, Lothar; Porter, Richard H.; Scharf, Sebastian H.; Kuennecke, Basil; Bruns, Andreas; Kienlin, Markus von; Harrison, Anthony C.; Paehler, Axel; Funk, Christoph (2015-04-01). "Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression". Journal of Pharmacology and Experimental Therapeutics. 353 (1): 213–233. doi:10.1124/jpet.114.222463. ISSN 0022-3565. PMID 25665805.
- ↑ "Basimglurant - AdisInsight". adisinsight.springer.com. Retrieved 2016-11-20.
- 1 2 "Roche - Pipeline". 2014. Retrieved 2014-08-01.
- 1 2 "Roche Group Development Pipeline" (PDF). 2014. Retrieved 2014-08-01.
- ↑ Lindemann, Lothar; Porter, Richard H.; Scharf, Sebastian H.; Kuennecke, Basil; Bruns, Andreas; von Kienlin, Markus; Harrison, Anthony C.; Paehler, Axel; Funk, Christoph (2015-04-01). "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): 213–233. doi:10.1124/jpet.114.222463. ISSN 1521-0103. PMID 25665805.
- ↑ "A Study of the Safety, Tolerability, and Pharmacokinetics of Multiple-Ascending Dose Basimglurant in Healthy Subjects and in Patients With Major Depressive Disorder (MDD) - Tabular View - ClinicalTrials.gov". clinicaltrials.gov. Retrieved 2016-11-20.
- ↑ Quiroz, Jorge A.; Tamburri, Paul; Deptula, Dennis; Banken, Ludger; Beyer, Ulrich; Rabbia, Michael; Parkar, Nikhat; Fontoura, Paulo; Santarelli, Luca (2016-07-01). "Efficacy and Safety of Basimglurant as Adjunctive Therapy for Major Depression". JAMA Psychiatry. 73 (7). doi:10.1001/jamapsychiatry.2016.0838. ISSN 2168-622X.
- ↑ "Roche abandons another Fragile X R&D program after PhII trials flunk out | FierceBiotech". www.fiercebiotech.com. Retrieved 2016-11-20.