RESUMEN
Point mutations in isocitrate dehydrogenase 1 (IDH1) result in conversion of α-ketoglutarate to the oncometabolite, d-2-hydroxyglutarate (2-HG). Ivosidenib is a once daily (QD), orally available, potent, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor approved for the treatment of patients with relapsed or refractory acute myeloid leukemia (AML) and intensive chemotherapy-ineligible newly diagnosed AML, with a susceptible IDH1 mutation. We characterized the protein binding, metabolism, metabolites, cell permeability, and drug-drug interaction potential of ivosidenib in humans, monkeys, dogs, rats, and/or mice in in vitro experiments. In vivo pharmacokinetic (PK) profiling and assessment of drug distribution and excretion was undertaken in rats, dogs, and monkeys administered single-dose ivosidenib. The PK/pharmacodynamic (PD) relationship between ivosidenib and 2-HG was analyzed in an mIDH1 xenograft mouse model. Ivosidenib was well absorbed, showed low clearance, and moderate to long terminal half-life (5.3-18.5 hours) in rats, dogs, and monkeys. Brain to plasma exposure ratio was low (2.3%), plasma protein binding was high, and oxidative metabolism was the major elimination pathway. Ivosidenib had high cell permeability and was identified as a substrate for P-glycoprotein. There was moderate induction of cytochrome P450 (P450) enzymes CYP3A4 and CYP2B6 but minimal P450 inhibition or autoinduction. Tumor 2-HG reduction appeared to be dose- and drug-exposure-dependent. Ivosidenib showed a favorable PK profile in several animal species, along with a clear PK/PD relationship demonstrating 2-HG inhibition that translated well to patients with AML. SIGNIFICANCE STATEMENT: Ivosidenib is a mutant IDH1 (mIDH1) inhibitor approved for the treatment of certain patients with mIDH1 acute myeloid leukemia. In Sprague-Dawley rats, beagle dogs, and cynomolgus monkeys, ivosidenib demonstrated a favorable pharmacokinetic profile, and in female BALB/c mice showed clear dose- and exposure-dependent inhibition of the oncometabolite, d-2-hydroxyglutarate, which is present at abnormal levels in mIDH1 tumors. These findings led to the further development of ivosidenib and are consistent with data from patients with mIDH1 cancers and healthy participants.
Asunto(s)
Glicina/análogos & derivados , Isocitrato Deshidrogenasa/metabolismo , Leucemia Mieloide Aguda , Piridinas/farmacocinética , Animales , Antineoplásicos/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Vías de Eliminación de Fármacos , Interacciones Farmacológicas , Glutaratos/metabolismo , Glicina/farmacocinética , Haplorrinos , Humanos , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Isocitrato Deshidrogenasa/genética , Ácidos Cetoglutáricos/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Tasa de Depuración Metabólica , Ratones , Mutación Puntual , Unión Proteica , Ratas , Ensayos Antitumor por Modelo de Xenoinjerto/métodosRESUMEN
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.
RESUMEN
Poor solubility and cationic amphiphilic drug-likeness were liabilities identified for a lead series of S1P3-sparing, S1P1 agonists originally developed from a high-throughput screening campaign. This work describes the subsequent optimization of these leads by balancing potency, selectivity, solubility and overall molecular charge. Focused SAR studies revealed favorable structural modifications that, when combined, produced compounds with overall balanced profiles. The low brain exposure observed in rat suggests that these compounds would be best suited for the potential treatment of peripheral autoimmune disorders.
Asunto(s)
Oxadiazoles/farmacología , Receptores de Lisoesfingolípidos/agonistas , Tiadiazoles/farmacología , Animales , Encéfalo/metabolismo , Ácido Glutámico/metabolismo , Células Hep G2 , Humanos , Enlace de Hidrógeno , Cinética , Oxadiazoles/sangre , Oxadiazoles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Tiadiazoles/sangre , Tiadiazoles/síntesis químicaRESUMEN
The discovery of a new series of selective S1P1 agonists is described. This series of piperazinyl-oxadiazole derivatives was rapidly optimized starting from high-throughput screening hit 1 to afford potent and selective lead compound 10d. Further SAR studies showed that 10d was converted to the active phosphate metabolite 29 in vivo. Oral administration of compound 10d to rats was shown to induce lymphopenia at 3 mg/kg.
Asunto(s)
Oxadiazoles/farmacología , Piperazinas/farmacología , Receptores de Lisoesfingolípidos/agonistas , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Femenino , Linfopenia/inducido químicamente , Linfopenia/patología , Estructura Molecular , Oxadiazoles/administración & dosificación , Oxadiazoles/química , Piperazinas/administración & dosificación , Piperazinas/química , Ratas , Ratas Endogámicas Lew , Receptores de Esfingosina-1-Fosfato , Relación Estructura-ActividadRESUMEN
Sequential allylation of chiral, nonracemic thiolactam 8 affords clean thio-Claisen [3,3] products 11. The stereoselectivity of the rearrangement was found to be on the order of 10-11:1, with the exo-endo products responsible for the mixture. Addition of hydride or methyllithium-cerium chloride gave clean addition to the thiolactam in the form of its iminium salts 12. Hydrolysis gave 4,4-dialkylcyclohexenones 15, which were cyclized to the cyclopentene derivatives 16 using Grubbs' catalyst.