GDC-0834
[(R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide]
is a potent, selective small molecule inhibitor of Bruton's tyrosine kinase
(BTK). Its development followed SAR studies on CGI-1746, another potent and selective
BTK inhbitor. GDC-0834 maintained the potency and selectivity of CGI-1746, but
with much improved PK in preclinical animal models. GDC-0834 inhibits BTK in vitro with an IC50 of 0.006 uM and has an EC50
of 0.060 uM in the cell based CD86 assay. In human whole blood, GDC-0834
demonstrated potent inhibition of both anti-IgE stimulated CD63 expression
(basophils) and anti-IgD stimulated CD69 expression (B-cells) with EC50’s
of 0.35 and 0.38 uM, respectively [1].
Appreciating its potential for the treatment of rheumatoid arthritis, a single dose IND was filed and GDC-0834 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, GDC-0834 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure.
The activity of GDC-0834 is as follows:
Appreciating its potential for the treatment of rheumatoid arthritis, a single dose IND was filed and GDC-0834 was taken in to a single dose phase I trial in healthy volunteers to quickly evaluate the human pharmacokinetics. In human, GDC-0834 was found to be highly labile at the exo-cyclic amide bond that links the tetrahydrobenzothiophene moiety to the central aniline ring, resulting in insufficient parent drug exposure.
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| GDC-0834: 2D and 3D Structure |
The activity of GDC-0834 is as follows:
IC50
(BTK enzyme assay) = 0.006 uM
EC50
(Cell Based CD86 assay) = 0.06 uM
Common Name: GDC-0834
Synonyms: GDC-0834; GDC-0834; GDC 0834
IUPAC Name: (R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
SMILES:O=C(C1=CC(CCCC2)=C2S1)NC3=CC=CC(C(N=C4NC5=CC=C([C@H]6N(C)CCN(C)C6=O)C=C5)=CN(C)C4=O)=C3C
CAS Number: 1133432-46-8
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor
Indication: Anti-Inflammatory Agent; Treatment of Rheumatoid Arthritis
Development Stage: Pre-Clinical
Company: Gilead Pharmaceutical/Genentech
References:
1. Young, W. B.; et. al. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett 2015, 25(6), 1333-1337 (synthesis and activity).
2. Blomgren, P. A.; et. al. Substituted amides, methods of making, use thereof for the treatment of diseases such as cancer. WO2009039397A2 (synthesis and activity)
Synonyms: GDC-0834; GDC-0834; GDC 0834
IUPAC Name: (R)-N-(3-(6-((4-(1,4-dimethyl-3-oxopiperazin-2-yl)phenyl)amino)-4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)-2-methylphenyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxamide
SMILES:O=C(C1=CC(CCCC2)=C2S1)NC3=CC=CC(C(N=C4NC5=CC=C([C@H]6N(C)CCN(C)C6=O)C=C5)=CN(C)C4=O)=C3C
CAS Number: 1133432-46-8
Mechanism of Action: Kinase Inhibitor; BTK Inhibitor
Indication: Anti-Inflammatory Agent; Treatment of Rheumatoid Arthritis
Development Stage: Pre-Clinical
Company: Gilead Pharmaceutical/Genentech
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| 1H NMR (Estimated) for GDC-0834 |
References:
1. Young, W. B.; et. al. Potent and selective Bruton's tyrosine kinase inhibitors: discovery of GDC-0834. Bioorg Med Chem Lett 2015, 25(6), 1333-1337 (synthesis and activity).
2. Blomgren, P. A.; et. al. Substituted amides, methods of making, use thereof for the treatment of diseases such as cancer. WO2009039397A2 (synthesis and activity)
