RESUMEN
ATR is a key kinase in the DNA-damage response (DDR) that is synthetic lethal with several other DDR proteins, making it an attractive target for the treatment of genetically selected solid tumors. Herein we describe the discovery of a novel ATR inhibitor guided by a pharmacophore model to position a key hydrogen bond. Optimization was driven by potency and selectivity over the related kinase mTOR, resulting in the identification of camonsertib (RP-3500) with high potency and excellent ADME properties. Preclinical evaluation focused on the impact of camonsertib on myelosuppression, and an exploration of intermittent dosing schedules to allow recovery of the erythroid compartment and mitigate anemia. Camonsertib is currently undergoing clinical evaluation both as a single agent and in combination with talazoparib, olaparib, niraparib, lunresertib, or gemcitabine (NCT04497116, NCT04972110, NCT04855656). A preliminary recommended phase 2 dose for monotherapy was identified as 160 mg QD given 3 days/week.
Asunto(s)
Neoplasias , Humanos , Proteínas de la Ataxia Telangiectasia Mutada , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , GemcitabinaRESUMEN
MK-0674 is a potent and selective cathepsin K inhibitor from the same structural class as odanacatib with a comparable inhibitory potency profile against Cat K. It is orally bioavailable and exhibits long half-life in pre-clinical species. In vivo studies using deuterated MK-0674 show stereoselective epimerization of the alcohol stereocenter via an oxidation/reduction cycle. From in vitro incubations, two metabolites could be identified: the hydroxyleucine and the glucuronide conjugate which were confirmed using authentic synthetic standards.
Asunto(s)
Compuestos de Bifenilo/administración & dosificación , Compuestos de Bifenilo/farmacocinética , Catepsina K/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/administración & dosificación , Inhibidores de Cisteína Proteinasa/farmacocinética , Descubrimiento de Drogas/métodos , Administración Oral , Animales , Disponibilidad Biológica , Compuestos de Bifenilo/química , Catepsina K/metabolismo , Inhibidores de Cisteína Proteinasa/química , Perros , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Humanos , Macaca mulatta , Conejos , RatasRESUMEN
Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib. Evaluation in dermal fibroblast culture showed minimal intracellular collagen accumulation relative to less selective Cat K inhibitors.
Asunto(s)
Compuestos de Bifenilo/farmacología , Catepsinas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Animales , Azepinas/química , Azepinas/farmacología , Catepsina K , Colágeno/efectos de los fármacos , Colágeno/inmunología , Perros , Fibroblastos/efectos de los fármacos , Humanos , Modelos Biológicos , Estructura Molecular , Osteoporosis Posmenopáusica/tratamiento farmacológico , Piel/citología , Relación Estructura-Actividad , Sulfonas/química , Sulfonas/farmacologíaRESUMEN
Highly potent, selective, and bioavailable inhibitors of human, mouse, or rat cathepsin S are described. The key structural features combine a sulfonyl moiety attached to a large group in P2 and a small substituent in P3.
Asunto(s)
Catepsinas/antagonistas & inhibidores , Química Farmacéutica/métodos , Animales , Inhibidores de Cisteína Proteinasa/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Unión Proteica , Ratas , Relación Estructura-ActividadRESUMEN
Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.