RESUMEN
A novel series of spirocyclic-diamine based, isoform non-selective inhibitors of acetyl-CoA carboxylase (ACC) is described. These spirodiamine derivatives were discovered by design of a library to mimic the structural rigidity and hydrogen-bonding pattern observed in the co-crystal structure of spirochromanone inhibitor I. The lead compound 3.5.1 inhibited de novo lipogenesis in rat hepatocytes, with an IC50 of 0.30 µM.
Asunto(s)
Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilasa/antagonistas & inhibidores , Descubrimiento de Drogas , Hepatocitos/efectos de los fármacos , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Animales , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hepatocitos/enzimología , Humanos , Concentración 50 Inhibidora , Modelos Biológicos , Estructura Molecular , Ratas , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacologíaRESUMEN
A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.
Asunto(s)
Diabetes Mellitus Tipo 2/enzimología , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/uso terapéutico , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Perros , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Fenetilaminas/química , Fenetilaminas/farmacología , Fenetilaminas/uso terapéutico , Piperidinas/química , Piperidinas/farmacología , Piperidinas/uso terapéutico , RatasRESUMEN
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Hepatocitos/efectos de los fármacos , Cetonas/metabolismo , Lipogénesis/efectos de los fármacos , Microsomas/efectos de los fármacos , Acetil-CoA Carboxilasa/metabolismo , Adulto , Animales , Área Bajo la Curva , Células Cultivadas , Estudios Cruzados , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Perros , Método Doble Ciego , Hepatocitos/citología , Humanos , Masculino , Malonil Coenzima A/metabolismo , Microsomas/metabolismo , Persona de Mediana Edad , Modelos Moleculares , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Relación Estructura-Actividad , Adulto JovenRESUMEN
Acetyl-CoA carboxylase (ACC) catalyzes the rate-determining step in de novo lipogenesis and plays a crucial role in the regulation of fatty acid oxidation. Alterations in lipid metabolism are believed to contribute to insulin resistance; thus inhibition of ACC offers a promising option for intervention in type 2 diabetes mellitus. Herein we disclose a series of ACC inhibitors based on a spirocyclic pyrazololactam core. The lactam series has improved chemical and metabolic stability relative to our previously reported pyrazoloketone series, while retaining potent inhibition of ACC1 and ACC2. Optimization of the pyrazole and amide substituents led to quinoline amide 21, which was advanced to preclinical development.
Asunto(s)
Acetil-CoA Carboxilasa/antagonistas & inhibidores , Lactamas/farmacología , Animales , Área Bajo la Curva , Lactamas/química , Espectroscopía de Resonancia MagnéticaRESUMEN
This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.