RESUMEN
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.
Asunto(s)
Exonucleasas/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/síntesis química , Inhibidores de Fosfodiesterasa/farmacología , Cromatografía Liquida , Humanos , Espectroscopía de Protones por Resonancia MagnéticaRESUMEN
Serine/threonine protein kinases Aurora A, B, and C play essential roles in cell mitosis and cytokinesis. Currently a number of Aurora kinase inhibitors with different isoform selectivities are being evaluated in the clinic. Herein we report the discovery and characterization of 21c (AC014) and 21i (AC081), two structurally novel, potent, kinome-selective pan-Aurora inhibitors. In the human colon cancer cell line HCT-116, both compounds potently inhibit histone H3 phosphorylation and cell proliferation while inducing 8N polyploidy. Both compounds administered intravenously on intermittent schedules displayed potent and durable antitumor activity in a nude rat HCT-116 tumor xenograft model and exhibited good in vivo tolerability. Taken together, these data support further development of both 21c and 21i as potential therapeutic agents for the treatment of solid tumors and hematological malignancies.
Asunto(s)
Acetanilidas/síntesis química , Antineoplásicos/síntesis química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Triazinas/síntesis química , Acetanilidas/farmacocinética , Acetanilidas/farmacología , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Aurora Quinasa A , Aurora Quinasas , Dominio Catalítico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Histonas/metabolismo , Humanos , Modelos Moleculares , Trasplante de Neoplasias , Fosforilación , Unión Proteica , Ratas , Ratas Desnudas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Trasplante Heterólogo , Triazinas/farmacocinética , Triazinas/farmacologíaRESUMEN
The synthesis and SAR for a novel series of pyrrolotriazines as pan-Aurora kinase inhibitors are described. Optimization of the cyclopropane carboxamide terminus of lead compound 1 resulted in analogs with high cellular activity and improved rat PK profiles. Notably, compound 17l demonstrated tumor growth inhibition in a mouse xenograft model.
Asunto(s)
Inhibidores de Proteínas Quinasas/farmacología , Triazinas/farmacología , Aurora Quinasas , Relación Dosis-Respuesta a Droga , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/síntesis química , Triazinas/químicaRESUMEN
Thien-2-yl 1S,2R-milnacipran analogues were synthesized and characterized as norepinephrine/serotonin transporter inhibitors. These compounds possessed higher potencies than 1S,2R-milnacipran (2R-1) while maintaining low molecular weight and moderate lipophilicity, which are the important features for the pharmacological and pharmacokinetic characteristics of milnacipran (1). Thus, compound 5c exhibited IC50 values of 2.3 and 32 nM, respectively, at NET and SERT, which were more than 10-fold better than those of 1 (NET IC50 = 77 nM, SERT IC50 = 420 nM). Moreover, 5c achieved the same efficacy as 1, but with much lower doses, in a rodent spinal nerve ligation pain model. In addition, 5c displayed desirable pharmacokinetic properties in several species, including high oral availability and significant brain penetration.
Asunto(s)
Ciclopropanos/farmacología , Neuralgia/tratamiento farmacológico , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Dimensión del Dolor/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Estereoisomerismo , Administración Oral , Animales , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/metabolismo , Ciclopropanos/farmacocinética , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Masculino , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Milnaciprán , Modelos Moleculares , Estructura Molecular , Peso Molecular , Neuralgia/patología , Ratas , Ratas Sprague-Dawley , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacocinética , Nervios Espinales/patología , Nervios Espinales/cirugía , Relación Estructura-ActividadRESUMEN
Compounds with various activities and selectivities were discovered through structure-activity relationship studies of bicifadine analogs as monoamine transporter inhibitors. The norepinephrine-selective 2-thienyl compound S-6j was efficacious in a rodent pain model.
Asunto(s)
Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Proteínas de Transporte de Neurotransmisores/química , Animales , Células CACO-2 , Química Farmacéutica/métodos , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Proteínas de Transporte de Membrana/química , Proteínas de Transporte de Membrana/farmacología , Modelos Químicos , Neurotransmisores/metabolismo , Proteínas de Transporte de Neurotransmisores/antagonistas & inhibidores , Norepinefrina/química , Dolor , Ratas , Relación Estructura-ActividadRESUMEN
A series of milnacipran analogs were synthesized and studied as monoamine transporter inhibitors, and several potent compounds with moderate lipophilicity were identified from the 1S,2R-isomers. Thus, 15l exhibited IC(50) values of 1.7nM at NET and 25nM at SERT, which were, respectively, 20- and 13-fold more potent than 1S,2R-milnacipran 1-II.
Asunto(s)
Antidepresivos/síntesis química , Antidepresivos/farmacología , Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Norepinefrina/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Antidepresivos/química , Técnicas Químicas Combinatorias , Ciclopropanos/química , Humanos , Concentración 50 Inhibidora , Milnaciprán , Estructura Molecular , Inhibidores Selectivos de la Recaptación de Serotonina/química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of milnacipran analogs containing a heteroaromatic group were synthesized and studied as monoamine transporter inhibitors. Many compounds exhibited higher potency than milnacipran at NET and NET/SERT with no significant change in lipophilicity. For example, compound R-26f was about 10-fold more potent than milnacipran with IC(50) values of 8.7 and 26nM at NET and SERT, respectively.
Asunto(s)
Ciclopropanos/síntesis química , Ciclopropanos/farmacología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/antagonistas & inhibidores , Inhibidores Selectivos de la Recaptación de Serotonina/síntesis química , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Técnicas Químicas Combinatorias , Ciclopropanos/química , Humanos , Milnaciprán , Estructura Molecular , Norepinefrina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/química , Relación Estructura-ActividadRESUMEN
Derivatives of milnacipran were synthesized and studied as monoamine transporter inhibitors. Potent analogs were discovered at NET (9k) and at both NET and SERT (9s and 9u). A pharmacophore model was established based on the conformational analysis of milnacipran in aqueous solution using NMR techniques and was consistent with the SAR results.
Asunto(s)
Ciclopropanos/química , Ciclopropanos/farmacología , Proteínas de Transporte Vesicular de Monoaminas/antagonistas & inhibidores , Acetamidas/química , Acetamidas/farmacología , Alquilación , Amidas/química , Amidas/farmacología , Indoles/química , Indoles/farmacología , Milnaciprán , Modelos Moleculares , Conformación Molecular , Resonancia Magnética Nuclear Biomolecular , Estereoisomerismo , Relación Estructura-Actividad , Proteínas de Transporte Vesicular de Monoaminas/químicaRESUMEN
The design, synthesis, and SAR of a series of substituted spirohydantoins are described. Optimization of an in-house screening hit gave compounds that exhibited potent binding affinity and functional activity at MCH-R1.
Asunto(s)
Fármacos Antiobesidad/síntesis química , Hidantoínas/síntesis química , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Compuestos de Espiro/síntesis química , Fármacos Antiobesidad/farmacología , Diseño de Fármacos , Humanos , Hidantoínas/farmacología , Cinética , Unión Proteica , Compuestos de Espiro/farmacología , Relación Estructura-ActividadRESUMEN
A series of thienopyrimidinone bis-aminopyrrolidine ureas were designed, synthesized, and evaluated for their ability to bind melanin-concentrating hormone receptor-1. These compounds exhibit potent binding affinity (K(i)=3 nM) and good in vitro metabolic stability.
Asunto(s)
Química Farmacéutica/métodos , Pirrolidinas/química , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Urea/química , Animales , Inhibidores del Citocromo P-450 CYP2D6 , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Cinética , Ratones , Modelos Químicos , Conformación Molecular , Unión Proteica , Relación Estructura-ActividadRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited potent binding affinity and functional activity at MCH-R1, and good oral bioavailability in rat.
Asunto(s)
Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Estructura Molecular , Pirrolidinas/química , Ratas , Receptores de la Hormona Hipofisaria/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacologíaRESUMEN
The design, synthesis, and SAR of a series of retro bis-aminopyrrolidine ureas are described. Compounds from this series exhibited considerable binding affinity (Ki = 1 nM) and functional activity at MCH-R1, acceptable CYP2D6 inhibition, and good rat brain exposure.
Asunto(s)
Pirrolidinas/química , Pirrolidinas/farmacología , Receptores de Somatostatina/antagonistas & inhibidores , Urea/análogos & derivados , Animales , Concentración 50 Inhibidora , Estructura Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacocinética , Ratas , Receptores de Somatostatina/metabolismo , Relación Estructura-Actividad , Urea/síntesis química , Urea/química , Urea/farmacocinética , Urea/farmacologíaRESUMEN
Melanin-concentrating hormone receptor antagonists containing thieno- and a benzopyridazinone cores were designed and tested as potential anorectic agents. These ligands showed high affinity for the receptor, potent functional activity in vitro, and good oral bioavailabilty in rats. The thiophene analogue exhibited low iv clearance, long half-life, and high brain penetration. In obese rats, the thienopyridazinone demonstrated a dose-dependent reduction in feeding and body weight with doses between 1 and 10 mg kg-1.
Asunto(s)
Depresores del Apetito/síntesis química , Piridazinas/síntesis química , Receptores de Somatostatina/antagonistas & inhibidores , Tiofenos/síntesis química , Animales , Depresores del Apetito/farmacocinética , Depresores del Apetito/farmacología , Disponibilidad Biológica , Peso Corporal/efectos de los fármacos , Encéfalo/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Semivida , Masculino , Obesidad/tratamiento farmacológico , Permeabilidad , Piridazinas/química , Piridazinas/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
A novel series of bis-aminopyrrolidine ureas containing either a 4-biphenylcarboxmide or 5-phenyl-2-thiophenecarboxamide group have been identified as potent and functional antagonists of the melanin-concentrating hormone receptor-1. Syntheses and SAR are described, which led to the discovery of compounds with high binding affinity (Ki = 1 nM) for the receptor. Preliminary in vitro metabolic stability data are also reported for key compounds.
Asunto(s)
Amidas , Pirrolidinas , Receptores de Somatostatina/antagonistas & inhibidores , Urea , Amidas/síntesis química , Amidas/farmacología , Animales , Diseño de Fármacos , Conformación Molecular , Peso Molecular , Pirrolidinas/síntesis química , Pirrolidinas/farmacología , Ratas , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/síntesis química , Urea/farmacologíaRESUMEN
Ureas derived from two substituted 3-aminopyrrolidine subunits were prepared as constrained analogs of a linear lead compound and tested as antagonists of the MCH(1) receptor. The series was optimized for substitution and stereochemistry to generate a functional antagonist with a K(i) of 3.3 nM and IC(50) of 12 nM (GTPgammaS).