2 research outputs found
Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents
We previously
reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM)
kinase, which is a target for novel radiosensitizing drugs. While
our initial lead, compound <b>4</b>, was relatively potent and
nontoxic, it exhibited poor stability to oxidative metabolism and
relatively poor selectivity against other kinases. The current study
focused on balancing potency and selectivity with metabolic stability
through structural modification to the metabolized site on the quinazoline
core. We performed extensive structure–activity and structure–property
relationship studies on this quinazoline ATM kinase inhibitor in order
to identify structural variants with enhanced selectivity and metabolic
stability. We show that, while the C-7-methoxy group is essential
for potency, replacing the C-6-methoxy group considerably improves
metabolic stability without affecting potency. Promising analogues <b>20</b>, <b>27g</b>, and <b>27n</b> were selected based
on in vitro pharmacology and evaluated in murine pharmacokinetic and
tolerability studies. Compound <b>27g</b> possessed significantly
improve pharmacokinetics relative to that of <b>4</b>. Compound <b>27g</b> was also significantly more selective against other kinases
than <b>4</b>. Therefore, <b>27g</b> is a good candidate
for further development as a potential radiosensitizer
Optimization of a Novel Series of Ataxia-Telangiectasia Mutated Kinase Inhibitors as Potential Radiosensitizing Agents
We previously
reported a novel inhibitor of the ataxia-telangiectasia mutated (ATM)
kinase, which is a target for novel radiosensitizing drugs. While
our initial lead, compound <b>4</b>, was relatively potent and
nontoxic, it exhibited poor stability to oxidative metabolism and
relatively poor selectivity against other kinases. The current study
focused on balancing potency and selectivity with metabolic stability
through structural modification to the metabolized site on the quinazoline
core. We performed extensive structure–activity and structure–property
relationship studies on this quinazoline ATM kinase inhibitor in order
to identify structural variants with enhanced selectivity and metabolic
stability. We show that, while the C-7-methoxy group is essential
for potency, replacing the C-6-methoxy group considerably improves
metabolic stability without affecting potency. Promising analogues <b>20</b>, <b>27g</b>, and <b>27n</b> were selected based
on in vitro pharmacology and evaluated in murine pharmacokinetic and
tolerability studies. Compound <b>27g</b> possessed significantly
improve pharmacokinetics relative to that of <b>4</b>. Compound <b>27g</b> was also significantly more selective against other kinases
than <b>4</b>. Therefore, <b>27g</b> is a good candidate
for further development as a potential radiosensitizer