Attempts to directly
drug the important oncogene KRAS have met
with limited success despite numerous efforts across industry and
academia. The KRASG12C mutant represents an “Achilles
heel” and has recently yielded to covalent targeting with small
molecules that bind the mutant cysteine and create an allosteric pocket
on GDP-bound RAS, locking it in an inactive state. A weak inhibitor
at this site was optimized through conformational locking of a piperazine–quinazoline
motif and linker modification. Subsequent introduction of a key methyl
group to the piperazine resulted in enhancements in potency, permeability,
clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species
pharmacokinetic parameters and in vivo efficacy.
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.
KRAS is an archetypal high-value
intractable oncology drug target.
The glycine to cysteine mutation at codon 12 represents an Achilles
heel that has now rendered this important GTPase druggable. Herein,
we report our structure-based drug design approach that led to the
identification of 21, AZD4625, a clinical development
candidate for the treatment of KRASG12C positive tumors.
Highlights include a quinazoline tethering strategy to lock out a
bio-relevant binding conformation and an optimization strategy focused
on the reduction of extrahepatic clearance mechanisms seen in preclinical
species. Crystallographic analysis was also key in helping to rationalize
unusual structure–activity relationship in terms of ring size
and enantio-preference. AZD4625 is a highly potent and selective inhibitor
of KRASG12C with an anticipated low clearance and high
oral bioavailability profile in humans.
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
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