2 research outputs found
Mitigation of Acetylcholine Esterase Activity in the 1,7-Diazacarbazole Series of Inhibitors of Checkpoint Kinase 1
Checkpoint
kinase 1 (ChK1) plays a key role in the DNA damage response, facilitating
cell-cycle arrest to provide sufficient time for lesion repair. This
leads to the hypothesis that inhibition of ChK1 might enhance the
effectiveness of DNA-damaging therapies in the treatment of cancer.
Lead compound <b>1</b> (GNE-783), the prototype of the 1,7-diazacarbazole
class of ChK1 inhibitors, was found to be a highly potent inhibitor
of acetylcholine esterase (AChE) and unsuitable for development. A
campaign of analogue synthesis established SAR delineating ChK1 and
AChE activities and allowing identification of new leads with improved
profiles. In silico docking using a model of AChE permitted rationalization
of the observed SAR. Compounds <b>19</b> (GNE-900) and <b>30</b> (GNE-145) were identified as selective, orally bioavailable
ChK1 inhibitors offering excellent in vitro potency with significantly
reduced AChE activity. In combination with gemcitabine, these compounds
demonstrate an in vivo pharmacodynamic effect and are efficacious
in a mouse p53 mutant xenograft model
Identification of <i>C</i>ā2 Hydroxyethyl Imidazopyrrolopyridines as Potent JAK1 Inhibitors with Favorable Physicochemical Properties and High Selectivity over JAK2
Herein we report on the structure-based
discovery of a <i>C</i>-2 hydroxyethyl moiety which provided
consistently high
levels of selectivity for JAK1 over JAK2 to the imidazopyrrolopyridine
series of JAK1 inhibitors. X-ray structures of a <i>C</i>-2 hydroxyethyl analogue in complex with both JAK1 and JAK2 revealed
differential ligand/protein interactions between the two isoforms
and offered an explanation for the observed selectivity. Analysis
of historical data from related molecules was used to develop a set
of physicochemical compound design parameters to impart desirable
properties such as acceptable membrane permeability, potent whole
blood activity, and a high degree of metabolic stability. This work
culminated in the identification of a highly JAK1 selective compound
(<b>31</b>) exhibiting favorable oral bioavailability across
a range of preclinical species and robust efficacy in a rat CIA model