Monday, December 14, 2015

Drugs in Clinical Pipeline: GDC-0834 | Treatment of Rheumatoid Arthritis | Antiinflammatory Agent | BTK Inhibitor

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.

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
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

1H NMR (Estimated) for GDC-0834

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)