RESUMEN
A series of novel thiazole-containing amides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent and selective PfFPPS/GGPPS inhibitors with good in vitro ADME profiles. The most promising candidate molecules were progressed to mouse in vivo PK studies and demonstrated adequate free drug exposure to warrant further investigation.
Asunto(s)
Antimaláricos/farmacología , Difosfonatos/farmacología , Inhibidores Enzimáticos/farmacología , Farnesiltransferasa/antagonistas & inhibidores , Geraniltranstransferasa/antagonistas & inhibidores , Plasmodium falciparum/efectos de los fármacos , Antimaláricos/síntesis química , Antimaláricos/química , Difosfonatos/síntesis química , Difosfonatos/química , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Farnesiltransferasa/metabolismo , Geraniltranstransferasa/metabolismo , Estructura Molecular , Pruebas de Sensibilidad Parasitaria , Plasmodium falciparum/enzimología , Relación Estructura-ActividadRESUMEN
Narcolepsy type 1 (Na-1) and 2 (Na-2) are characterized by an inability to sustain wakefulness and are likely caused by degeneration of orexin neurons. Near complete orexin neurodegeneration depletes orexin-A from the cerebrospinal fluid and produces Na-1. The pathophysiology of Na-2 is less understood but has been hypothesized to be due to less extensive loss of orexin neurotransmission. The orexin-tTA; TetO diphtheria toxin A mouse allows conditional control over the extent and timing of orexin neurodegeneration. To evaluate partial ablation of the orexin field as a model of Na-2, orexin-A positive cell counts and sleep/wake phenotypes (determined by piezoelectric monitoring) were correlated within individual mice after different protocols of diet-controlled neurodegeneration. Partial ablations that began during the first 8 days of study were 14% larger than partial ablations induced during the last 8 days of study, 6 weeks later and prior to sacrifice of all mice, suggesting orexin-A positive cell death continued despite the resumption of conditions intended to keep orexin neurons intact. Sleep/wake of mice with 71.0% orexin-A positive cell loss, initiated at the beginning of study, resembled that of orexin-intact controls more than mice with near complete neurodegeneration. Conversely, mice with 56.6% orexin-A positive cell loss, created at the end of study, had sleep/wake phenotypes that were similar to those of mice with near complete orexin-A positive cell loss. Collectively, these results suggest that compensatory wake-promotion develops in mice that have some critical portion of their orexinergic system remaining after partial ablation.
Asunto(s)
Modelos Animales de Enfermedad , Narcolepsia/genética , Enfermedades Neurodegenerativas/genética , Orexinas/genética , Fenotipo , Animales , Femenino , Masculino , Ratones , Ratones Transgénicos , Narcolepsia/metabolismo , Narcolepsia/fisiopatología , Enfermedades Neurodegenerativas/metabolismo , Neuronas/fisiología , Neuropéptidos/deficiencia , Neuropéptidos/genética , Orexinas/deficiencia , Sueño/fisiología , Vigilia/fisiologíaRESUMEN
A series of novel carbazole-containing amides and ureas were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the desired pharmacokinetic/pharmacodynamic parameters and the results of efficacy studies in db/db mice, compound 50 was selected for further profiling.
Asunto(s)
Amidas/farmacología , Carbazoles/farmacología , Criptocromos/metabolismo , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Urea/farmacología , Amidas/síntesis química , Amidas/química , Animales , Carbazoles/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Relación Dosis-Respuesta a Droga , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Estructura Molecular , Obesidad/tratamiento farmacológico , Relación Estructura-Actividad , Urea/análogos & derivados , Urea/químicaRESUMEN
A series of novel carbazole-containing sulfonamides and sulfamides were synthesized. A structure-activity relationship study of these compounds led to the identification of potent cryptochrome modulators. Based on the results of efficacy studies in diet-induced obese (DIO) mice, and the desired pharmacokinetic parameters, compound 41 was selected for further profiling.
Asunto(s)
Carbazoles/química , Criptocromos/química , Hipoglucemiantes/química , Sulfonamidas/química , Animales , Glucemia/análisis , Línea Celular Tumoral , Criptocromos/genética , Criptocromos/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/patología , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Relación Estructura-Actividad , Sulfonamidas/farmacología , Sulfonamidas/uso terapéuticoRESUMEN
The design of potent Pin1 inhibitors has been challenging because its active site specifically recognizes a phospho-protein epitope. The de novo design of phosphate-based Pin1 inhibitors focusing on the phosphate recognition pocket and the successful replacement of the phosphate group with a carboxylate have been previously reported. The potency of the carboxylate series is now further improved through structure-based optimization of ligand-protein interactions in the proline binding site which exploits the H-bond interactions necessary for Pin1 catalytic function. Further optimization using a focused library approach led to the discovery of low nanomolar non-phosphate small molecular Pin1 inhibitors. Structural modifications designed to improve cell permeability resulted in Pin1 inhibitors with low micromolar anti-proliferative activities against cancer cells.
Asunto(s)
Bencimidazoles/farmacología , Ácidos Carboxílicos/farmacología , Inhibidores Enzimáticos/farmacología , Isomerasa de Peptidilprolil/antagonistas & inhibidores , Fosfatos/química , Bencimidazoles/síntesis química , Bencimidazoles/química , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Dominio Catalítico/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Peptidilprolil Isomerasa de Interacción con NIMA , Isomerasa de Peptidilprolil/metabolismo , Relación Estructura-ActividadRESUMEN
Glucokinase activators are a class of experimental agents under investigation as a therapy for Type 2 diabetes mellitus. An X-ray crystal structure of a modestly potent agent revealed the potential to substitute the common heterocyclic amide donor-acceptor motif for a pyridone moiety. We have successfully demonstrated that both pyridone and pyrimidone heterocycles can be used as a potent donor-acceptor substituent. Several sub-micromolar analogs that possess the desired partial activator profile were synthesized and characterized. Unfortunately, the most potent activators suffered from sub-optimal pharmacokinetic properties. Nonetheless, these donor-acceptor motifs may find utility in other glucokinase activator series or beyond.
Asunto(s)
Activadores de Enzimas/química , Glucoquinasa/metabolismo , Pirimidinonas/síntesis química , Regulación Alostérica , Secuencias de Aminoácidos , Animales , Sitios de Unión , Modelos Moleculares , Pirimidinonas/química , RatasRESUMEN
As part of a strategy to deliver short-acting calcium-sensing receptor (CaSR) antagonists, the metabolically labile thiomethyl functionality was incorporated into the zwitterionic amino alcohol derivative 3 with the hope of increasing human clearance through oxidative metabolism, while delivering a pharmacologically inactive sulfoxide metabolite. The effort led to the identification of thioanisoles 22 and 23 as potent and orally active CaSR antagonists with a rapid onset of action and short pharmacokinetic half-lives, which led to a rapid and transient stimulation of parathyroid hormone in a dose-dependent fashion following oral administration to rats. On the basis of the balance between target pharmacology, safety, and human disposition profiles, 22 and 23 were advanced as clinical candidates for the treatment of osteoporosis.
RESUMEN
The development of a series of novel 1,2,3,4-tetrahydroisoquinolin-1-ones as antagonists of G protein-coupled receptor 40 (GPR40) is described. The synthesis, in vitro inhibitory values for GPR40, in vitro microsomal clearance and rat in vivo clearance data are discussed. Initial hits displayed high rat in vivo clearances that were higher than liver blood flow. Optimization of rat in vivo clearance was achieved and led to the identification of 15i, whose rat oral pharmacokinetic data is reported.
Asunto(s)
Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/química , Tetrahidroisoquinolinas/síntesis química , Tetrahidroisoquinolinas/farmacocinética , Administración Oral , Animales , Química Farmacéutica/métodos , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Humanos , Concentración 50 Inhibidora , Ligandos , Tasa de Depuración Metabólica , Modelos Químicos , Ratas , Relación Estructura-Actividad , Tetrahidroisoquinolinas/químicaRESUMEN
The development of a series of novel 4-substituted-2-aminopyrimidines as inhibitors of c-Jun N-terminal kinases is described. The synthesis, in vitro inhibitory values for JNK1, and the in vitro inhibitory value for a c-Jun cellular assay are discussed. Optimization of microsomal clearance led to the identification of 9c, whose kinase selectivity is reported.
Asunto(s)
Proteínas Quinasas JNK Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/síntesis química , Pirimidinas/farmacología , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Proteína Quinasa 8 Activada por Mitógenos/antagonistas & inhibidores , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Relación Estructura-ActividadRESUMEN
A series of pyridine ether PPAR agonists were synthesized through an ADDP and PS-PPh3 modified Mitsunobu protocol, which eliminated significant by-product formation. This method proved to be versatile, efficient and amenable to parallel synthesis.
RESUMEN
A series of novel pyridine-2-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compound (S)-13 was selected for further profiling.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Piridinas/química , Piridinas/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/patología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Masculino , Ratones , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Piridinas/síntesis química , Piridinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
A series of novel pyridine-3-propanoic acids was synthesized. A structure-activity relationship study of these compounds led to the identification of potent dual PPARalpha/gamma agonists with varied isoform selectivity. Based on the results of efficacy studies in diabetic (db/db) mice, and the desired pharmacokinetic parameters, compounds (S)-14 and (S)-19 were selected for further profiling.
Asunto(s)
Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Piridinas/sangre , Piridinas/farmacología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Línea Celular Tumoral , Diabetes Mellitus/sangre , Diabetes Mellitus/tratamiento farmacológico , Diabetes Mellitus/patología , Éter/química , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ratones , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Piridinas/síntesis química , Piridinas/uso terapéutico , Relación Estructura-Actividad , Tiazolidinedionas/químicaRESUMEN
In only seven steps a formal synthesis of enantiomerically enriched (+)-anatoxin-a has been achieved. This was accomplished by utilizing a highly enantioselective desymmetrization of the eight-membered ring ketone 1 to form 2, and a novel cascade reaction to construct the 9-azabicyclo[4.2.1]nonane skeleton.