RÉSUMÉ
Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed.
Sujet(s)
Tests de criblage à haut débit , Pyruvate kinase , Pyruvate kinase/métabolisme , Pyruvate kinase/antagonistes et inhibiteurs , Humains , Découverte de médicament , Relation structure-activité , Urée/composition chimique , Urée/pharmacologie , Activateurs d'enzymes/pharmacologie , Activateurs d'enzymes/composition chimique , Activateurs d'enzymes/synthèse chimique , Structure moléculaire , AnimauxRÉSUMÉ
Direct pharmacological inhibition of RAS has remained elusive, and efforts to target CRAF have been challenging due to the complex nature of RAF signaling, downstream of activated RAS, and the poor overall kinase selectivity of putative RAF inhibitors. Herein, we describe 15 (LXH254, Aversa, R.; et al. Int. Patent WO2014151616A1, 2014), a selective B/C RAF inhibitor, which was developed by focusing on drug-like properties and selectivity. Our previous tool compound, 3 (RAF709; Nishiguchi, G. A.; et al. J. Med. Chem. 2017, 60, 4969), was potent, selective, efficacious, and well tolerated in preclinical models, but the high human intrinsic clearance precluded further development and prompted further investigation of close analogues. A structure-based approach led to a pyridine series with an alcohol side chain that could interact with the DFG loop and significantly improved cell potency. Further mitigation of human intrinsic clearance and time-dependent inhibition led to the discovery of 15. Due to its excellent properties, it was progressed through toxicology studies and is being tested in phase 1 clinical trials.
Sujet(s)
Antinéoplasiques/composition chimique , Découverte de médicament/méthodes , Mutation/génétique , Inhibiteurs de protéines kinases/composition chimique , Protéines proto-oncogènes B-raf/antagonistes et inhibiteurs , Protéines proto-oncogènes B-raf/génétique , Animaux , Antinéoplasiques/pharmacologie , Conception de médicament , Découverte de médicament/tendances , Humains , Simulation de docking moléculaire/méthodes , Simulation de docking moléculaire/tendances , Mutation/effets des médicaments et des substances chimiques , Inhibiteurs de protéines kinases/pharmacologie , Tests d'activité antitumorale sur modèle de xénogreffe/méthodesRÉSUMÉ
Utilizing the already described 3,4-bi-aryl pyridine series as a starting point, incorporation of a second ring system with a hydrogen bond donor and additional hydrophobic contacts yielded the azaindole series which exhibited potent, picomolar RSK2 inhibition and the most potent in vitro target modulation seen thus far for a RSK inhibitor. In the context of the more potent core, several changes at the phenol moiety were assessed to potentially find a tool molecule appropriate for in vivo evaluation.
Sujet(s)
Inhibiteurs de protéines kinases/synthèse chimique , Inhibiteurs de protéines kinases/pharmacologie , Animaux , Chromatographie en phase liquide , Conception de médicament , Humains , Spectrométrie de masse , Phénols/pharmacologie , Inhibiteurs de protéines kinases/composition chimique , Spectroscopie par résonance magnétique du proton , Relation structure-activitéRÉSUMÉ
RAS oncogenes have been implicated in >30% of human cancers, all representing high unmet medical need. The exquisite dependency on CRAF kinase in KRAS mutant tumors has been established in genetically engineered mouse models and human tumor cells. To date, many small molecule approaches are under investigation to target CRAF, yet kinase-selective and cellular potent inhibitors remain challenging to identify. Herein, we describe 14 (RAF709) [ Aversa , Biaryl amide compounds as kinase inhibitors and their preparation . WO 2014151616, 2014 ], a selective B/C RAF inhibitor, which was developed through a hypothesis-driven approach focusing on drug-like properties. A key challenge encountered in the medicinal chemistry campaign was maintaining a balance between good solubility and potent cellular activity (suppression of pMEK and proliferation) in KRAS mutant tumor cell lines. We investigated the small molecule crystal structure of lead molecule 7 and hypothesized that disruption of the crystal packing would improve solubility, which led to a change from N-methylpyridone to a tetrahydropyranyl oxy-pyridine derivative. 14 proved to be soluble, kinase selective, and efficacious in a KRAS mutant xenograft model.
Sujet(s)
2,2'-Bipyridine/analogues et dérivés , Antinéoplasiques/pharmacologie , Benzamides/pharmacologie , Kinases raf/antagonistes et inhibiteurs , Protéines G ras/génétique , 2,2'-Bipyridine/composition chimique , 2,2'-Bipyridine/pharmacologie , Animaux , Antinéoplasiques/composition chimique , Antinéoplasiques/pharmacocinétique , Benzamides/composition chimique , Cristallographie aux rayons X , Chiens , Conception de médicament , Découverte de médicament , Stabilité de médicament , Humains , Concentration inhibitrice 50 , Souris , Thérapie moléculaire ciblée , Tumeurs/traitement médicamenteux , Tumeurs/génétique , Protéines proto-oncogènes B-raf/composition chimique , Protéines proto-oncogènes p21(ras)/génétique , Rats , Relation structure-activité , Tests d'activité antitumorale sur modèle de xénogreffeRÉSUMÉ
While the p90 ribosomal S6 kinase (RSK) family has been implicated in multiple tumor cell functions, the full understanding of this kinase family has been restricted by the lack of highly selective inhibitors. A bis-phenol pyrazole was identified from high-throughput screening as an inhibitor of the N-terminal kinase of RSK2. Structure-based drug design using crystallography, conformational analysis, and scaffold morphing resulted in highly optimized difluorophenol pyridine inhibitors of the RSK kinase family as demonstrated cellularly by the inhibition of YB1 phosphorylation. These compounds provide for the first time in vitro tools with an improved selectivity and potency profile to examine the importance of RSK signaling in cancer cells and to fully evaluate RSK as a therapeutic target.
Sujet(s)
Pyrazoles/composition chimique , Pyridines/composition chimique , Pyrimidines/composition chimique , Ribosomal Protein S6 Kinases, 90-kDa/antagonistes et inhibiteurs , Animaux , Lignée cellulaire , Cristallographie aux rayons X , Humains , Mâle , Souris , Modèles moléculaires , Phosphorylation , Conformation des protéines , Pyrazoles/synthèse chimique , Pyrazoles/pharmacologie , Pyridines/synthèse chimique , Pyridines/pharmacologie , Pyrimidines/synthèse chimique , Pyrimidines/pharmacologie , Rat Sprague-Dawley , Transduction du signal , Relation structure-activité , Protéine-1 de liaison à la boîte Y/métabolismeRÉSUMÉ
Compound 13 was discovered through morphing of the ATR biochemical HTS hit 1. The ABI series was potent and selective for ATR. Incorporation of a 6-azaindole afforded a marked increase in cellular potency but was associated with poor PK and hERG ion channel inhibition. DMPK experiments established that CYP P450 and AO metabolism in conjunction with Pgp and BCRP efflux were major causative mechanisms for the observed PK. The series also harbored the CYP3A4 TDI liability driven by the presence of both a morpholine and an indole moiety. Incorporation of an adjacent fluorine or nitrogen into the 6-azaindole addressed many of the various medicinal chemistry issues encountered.
RÉSUMÉ
The discovery of a novel series of pyrrolopyrazines as JAK inhibitors with comparable enzyme and cellular activity to tofacitinib is described. The series was identified using a scaffold hopping approach aided by structure based drug design using principles of intramolecular hydrogen bonding for conformational restriction and targeting specific pockets for modulating kinase activity.
Sujet(s)
Janus kinase 3/antagonistes et inhibiteurs , Inhibiteurs de protéines kinases/composition chimique , Inhibiteurs de protéines kinases/pharmacologie , Pyrazines/composition chimique , Pyrroles/composition chimique , Conception de médicament , Humains , Janus kinase 3/métabolisme , Modèles moléculaires , Conformation moléculaire , Structure moléculaire , Phosphorylation , Pipéridines/pharmacologie , Pyrimidines/pharmacologie , Pyrroles/pharmacologie , Relation structure-activitéRÉSUMÉ
2-Amino-7-substituted benzoxazole analogs were identified by HTS as inhibitors of RSK2. Molecular modeling and medicinal chemistry techniques were employed to explore the SAR for this series with a focus of improving in vitro and target modulation potency and physicochemical properties.
Sujet(s)
Benzoxazoles/composition chimique , Inhibiteurs de protéines kinases/composition chimique , Ribosomal Protein S6 Kinases, 90-kDa/antagonistes et inhibiteurs , Benzoxazoles/synthèse chimique , Benzoxazoles/métabolisme , Sites de fixation , Cristallographie aux rayons X , Humains , Simulation de dynamique moléculaire , Liaison aux protéines , Inhibiteurs de protéines kinases/synthèse chimique , Structure tertiaire des protéines , Ribosomal Protein S6 Kinases, 90-kDa/métabolisme , Relation structure-activitéRÉSUMÉ
The introduction of N-substituted pyrazoles in a new series of CCR5 antagonists was shown to substantially increase antiviral activity.
Sujet(s)
Agents antiVIH/composition chimique , Antagonistes des récepteurs CCR5 , Pyrazoles/composition chimique , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , Humains , Pyrazoles/synthèse chimique , Pyrazoles/pharmacologie , Récepteurs CCR5/métabolisme , Relation structure-activitéRÉSUMÉ
Starting with a high-throughput screening lead, a novel series of CCR5 antagonists was developed utilizing an information-based approach. Improvement of pharmacokinetic properties for the series was pursued by SAR exploration of the lead template. The synthesis, SAR and biological profiles of the series are described.
Sujet(s)
Agents antiVIH/composition chimique , Benzamides/composition chimique , Antagonistes des récepteurs CCR5 , Inhibiteurs de fusion du VIH/composition chimique , Pyrroles/composition chimique , Animaux , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacocinétique , Benzamides/synthèse chimique , Benzamides/pharmacologie , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacocinétique , Humains , Microsomes du foie/métabolisme , Pyrroles/synthèse chimique , Pyrroles/pharmacocinétique , Rats , Récepteurs CCR5/métabolisme , Relation structure-activitéRÉSUMÉ
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the 3-amino-8-azabicyclo[3.2.1]octane found in the CCR5 antagonist maraviroc.
Sujet(s)
Agents antiVIH/composition chimique , Composés azabicycliques/composition chimique , Antagonistes des récepteurs CCR5 , Cyclohexanes/composition chimique , Inhibiteurs de fusion du VIH/composition chimique , Triazoles/composition chimique , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , Lignée cellulaire tumorale , Cyclohexanes/synthèse chimique , Cyclohexanes/pharmacologie , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacologie , Humains , Maraviroc , Modèles chimiques , Récepteurs CCR5/métabolisme , Triazoles/synthèse chimique , Triazoles/pharmacologieRÉSUMÉ
The bicyclic 5-amino-3-azabicyclo[3.3.0]octanes were shown to be effective replacements for the conformationally restricted 4-aminopiperidine ring found in several series of CCR5 antagonists.
Sujet(s)
Antagonistes des récepteurs CCR5 , Évaluation préclinique de médicament , Pipéridines/composition chimique , Modèles moléculairesRÉSUMÉ
Replacement of a secondary amide with an N-acyl or N-sulfonyl gem-disubstituted azacyle in a series of CCR5 antagonists led to the identification of compounds with excellent in vitro HIV antiviral activity and increased intrinsic membrane permeability.
Sujet(s)
Amides/composition chimique , Agents antiVIH/composition chimique , Composés aza/composition chimique , Antagonistes des récepteurs CCR5 , Inhibiteurs de fusion du VIH/composition chimique , Agents antiVIH/synthèse chimique , Agents antiVIH/pharmacologie , Composés aza/synthèse chimique , Composés aza/pharmacologie , Lignée cellulaire tumorale , Perméabilité des membranes cellulaires/effets des médicaments et des substances chimiques , Inhibiteurs de fusion du VIH/synthèse chimique , Inhibiteurs de fusion du VIH/pharmacologie , Humains , Récepteurs CCR5/métabolismeRÉSUMÉ
A novel series of CCR5 antagonists has been identified, utilizing leads from high-throughput screening which were further modified based on insights from competitor molecules. Lead optimization was pursued by balancing opposing trends of metabolic stability and potency. Selective and potent analogs with good pharmacokinetic properties were successfully developed.
Sujet(s)
Antagonistes des récepteurs CCR5 , Pipéridines/composition chimique , Pipéridines/pharmacologie , Récepteurs CCR5/métabolisme , Animaux , Cellules Caco-2 , Chiens , Haplorhini , Humains , Pipéridines/pharmacocinétique , Rats , Spiranes/composition chimique , Spiranes/pharmacocinétique , Spiranes/pharmacologie , Relation structure-activitéRÉSUMÉ
A series of 7-[(5R)-substituted 2-oxo-1-pyrrolidinyl]-heptanoic acids were prepared, their isomeric purity determined, and pharmacologically evaluated. Lactams with affinity for the EP(4) receptor displayed agonist behavior. The lower side-chain of the lactam template could be substituted to afford ligands (e.g., 17, 24, 30, 31, and 33) of high potency and greater than 1000-fold affinity for EP(4) versus the other EP prostanoid receptors.
Sujet(s)
Lactames/composition chimique , Pyrrolidones/composition chimique , Récepteur prostaglandine E/agonistes , Lactames/métabolisme , Liaison aux protéines , Pyrrolidones/métabolisme , Récepteur prostaglandine E/métabolisme , Sous-type EP4 des récepteurs des prostaglandines E , StéréoisomérieRÉSUMÉ
A novel series of orally active pyrimido[5,4-3][1,2,4]triazine-5,7-diamine-based hypoglycemic agents have been identified. These compounds show non-selective inhibitory properties against a panel of protein tyrosine phosphatases including PTP1B. Compounds 12 and 13 display oral glucose lowering effects in ob/ob mice.