GDC-0834   Click here for help

GtoPdb Ligand ID: 9263

Synonyms: GDC 0834
PDB Ligand Immunopharmacology Ligand
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.
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Ligand Activity Visualisation Charts

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2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 8
Hydrogen bond donors 2
Rotatable bonds 7
Topological polar surface area 127.81
Molecular weight 596.26
XLogP 4.25
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

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Canonical SMILES CN1CCN(C(=O)C1c1ccc(cc1)Nc1nc(cn(c1=O)C)c1cccc(c1C)NC(=O)c1cc2c(s1)CCCC2)C
Isomeric SMILES CN1CCN(C(=O)[C@H]1c1ccc(cc1)Nc1nc(cn(c1=O)C)c1cccc(c1C)NC(=O)c1cc2c(s1)CCCC2)C
InChI InChI=1S/C33H36N6O3S/c1-20-24(9-7-10-25(20)36-31(40)28-18-22-8-5-6-11-27(22)43-28)26-19-39(4)33(42)30(35-26)34-23-14-12-21(13-15-23)29-32(41)38(3)17-16-37(29)2/h7,9-10,12-15,18-19,29H,5-6,8,11,16-17H2,1-4H3,(H,34,35)(H,36,40)/t29-/m1/s1
InChI Key CDOOFZZILLRUQH-GDLZYMKVSA-N
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]