Synonyms: GDC 0834
Compound class:
Synthetic organic
Comment: GDC-0834 was identified as a clinical candidate antiinflammatory Bruton's tyrosine kinase (BTK) inhibitor, through SAR guided improvements to the pharmacokinetic (PK) properties of the potent and selective BTK inhibitor CGI1746 [4]. GDC-0834 retains CGI1746's selectivity but exhibits significantly improved PK in preclinical animal models [1]. Studies suggest the involvement of aldehyde oxidase (AO) in the rapid amide hydrolysis of GDC-0834 to an inactive metabolite [3], which severly impacted on its ability to sustain beneficial clinical effects. Significant species difference in AO-induced inactivation of GDC-0834 are reported and explain why this was not picked up during preclinical studies [2]. Clinical development was terminated, with the manufacturer using insight gained to inform their search for improved inhibitors.
Ligand Activity Visualisation ChartsThese are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts. ✖ |
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References |
1. Liu L, Di Paolo J, Barbosa J, Rong H, Reif K, Wong H. (2011)
Antiarthritis effect of a novel Bruton's tyrosine kinase (BTK) inhibitor in rat collagen-induced arthritis and mechanism-based pharmacokinetic/pharmacodynamic modeling: relationships between inhibition of BTK phosphorylation and efficacy. J Pharmacol Exp Ther, 338 (1): 154-63. [PMID:21521773] |
2. Liu L, Halladay JS, Shin Y, Wong S, Coraggio M, La H, Baumgardner M, Le H, Gopaul S, Boggs J et al.. (2011)
Significant species difference in amide hydrolysis of GDC-0834, a novel potent and selective Bruton's tyrosine kinase inhibitor. Drug Metab Dispos, 39 (10): 1840-9. [PMID:21742900] |
3. Sodhi JK, Wong S, Kirkpatrick DS, Liu L, Khojasteh SC, Hop CE, Barr JT, Jones JP, Halladay JS. (2015)
A novel reaction mediated by human aldehyde oxidase: amide hydrolysis of GDC-0834. Drug Metab Dispos, 43 (6): 908-15. [PMID:25845827] |
4. Young WB, Barbosa J, Blomgren P, Bremer MC, Crawford JJ, Dambach D, Gallion S, Hymowitz SG, Kropf JE, Lee SH et al.. (2015)
Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett, 25 (6): 1333-7. [PMID:25701252] |