7 research outputs found
Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design
The discovery of a highly potent
and selective small molecule inhibitor <b>9</b> for in vitro
target validation of MNK1/2 kinases is described.
The aminopyrazine benzimidazole series was derived from an HTS hit
and optimized by utilization of a docking model, conformation analysis,
and binding pocket comparison against antitargets
Discovery of a Selective and Potent Inhibitor of Mitogen-Activated Protein Kinase-Interacting Kinases 1 and 2 (MNK1/2) Utilizing Structure-Based Drug Design
The discovery of a highly potent
and selective small molecule inhibitor <b>9</b> for in vitro
target validation of MNK1/2 kinases is described.
The aminopyrazine benzimidazole series was derived from an HTS hit
and optimized by utilization of a docking model, conformation analysis,
and binding pocket comparison against antitargets
Discovery of RAF265: A Potent mut-B-RAF Inhibitor for the Treatment of Metastatic Melanoma
Abrogation of errant signaling along
the MAPK pathway through the
inhibition of B-RAF kinase is a validated approach for the treatment
of pathway-dependent cancers. We report the development of imidazo-benzimidazoles
as potent B-RAF inhibitors. Robust <i>in vivo</i> efficacy
coupled with correlating pharmacokinetic/pharmacodynamic (PKPD) and
PD-efficacy relationships led to the identification of RAF265, <b>1</b>, which has advanced into clinical trials
Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3
In an effort to identify
new antidiabetic agents, we have discovered
a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine
analogues which are inhibitors of human glycogen synthase kinase 3
(GSK3). We developed efficient synthetic routes to explore a wide
variety of substitution patterns and convergently access a diverse
array of analogues. Compound <b>1</b> (CHIR-911, CT-99021, or
CHIR-73911) emerged from an exploration of heterocycles at the C-5
position, phenyl groups at C-4, and a variety of differently substituted
linker and aminopyridine moieties attached at the C-2 position. These
compounds exhibited GSK3 IC<sub>50</sub>s in the low nanomolar range
and excellent selectivity. They activate glycogen synthase in insulin
receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation
of lead compounds <b>1</b> and <b>2</b> (CHIR-611 or CT-98014)
in rodent models of type 2 diabetes revealed that single oral doses
lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose
transport, and improved glucose disposal without increasing insulin
levels
Synthesis, Binding Mode, and Antihyperglycemic Activity of Potent and Selective (5-Imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine Inhibitors of Glycogen Synthase Kinase 3
In an effort to identify
new antidiabetic agents, we have discovered
a novel family of (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)[2-(2-pyridylamino)ethyl]amine
analogues which are inhibitors of human glycogen synthase kinase 3
(GSK3). We developed efficient synthetic routes to explore a wide
variety of substitution patterns and convergently access a diverse
array of analogues. Compound <b>1</b> (CHIR-911, CT-99021, or
CHIR-73911) emerged from an exploration of heterocycles at the C-5
position, phenyl groups at C-4, and a variety of differently substituted
linker and aminopyridine moieties attached at the C-2 position. These
compounds exhibited GSK3 IC<sub>50</sub>s in the low nanomolar range
and excellent selectivity. They activate glycogen synthase in insulin
receptor-expressing CHO-IR cells and primary rat hepatocytes. Evaluation
of lead compounds <b>1</b> and <b>2</b> (CHIR-611 or CT-98014)
in rodent models of type 2 diabetes revealed that single oral doses
lowered hyperglycemia within 60 min, enhanced insulin-stimulated glucose
transport, and improved glucose disposal without increasing insulin
levels
Discovery and Evaluation of Clinical Candidate IDH305, a Brain Penetrant Mutant IDH1 Inhibitor
Inhibition
of mutant IDH1 is being evaluated clinically as a promising
treatment option for various cancers with hotspot mutation at Arg<sup>132</sup>. Having identified an allosteric, induced pocket of IDH1<sup>R132H</sup>, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones
as mutant IDH1 inhibitors for <i>in vivo</i> modulation
of 2-HG production and potential brain penetration. We report here
optimization efforts toward the identification of clinical candidate <b>IDH305</b> (<b>13</b>), a potent and selective mutant IDH1
inhibitor that has demonstrated brain exposure in rodents. Preclinical
characterization of this compound exhibited <i>in vivo</i> correlation of 2-HG reduction and efficacy in a patient-derived
IDH1 mutant xenograft tumor model. <b>IDH305</b> (<b>13</b>) has progressed into human clinical trials for the treatment of
cancers with IDH1 mutation
Design, Structure–Activity Relationship, and in Vivo Characterization of the Development Candidate NVP-HSP990
Utilizing
structure-based drug design, a novel dihydropyridopyrimidinone
series which exhibited potent Hsp90 inhibition, good pharmacokinetics
upon oral administration, and an excellent pharmacokinetic/pharmacodynamic
relationship in vivo was developed from a commercial hit. The exploration
of this series led to the selection of NVP-HSP990 as a development
candidate