RESUMEN
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Asunto(s)
Ácidos Carboxílicos/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Quinolonas/farmacología , Animales , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Diacilglicerol O-Acetiltransferasa/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Ratones , Modelos Moleculares , Estructura Molecular , Quinolonas/síntesis química , Quinolonas/química , Relación Estructura-ActividadRESUMEN
A novel series of benzimidazolone-containing histamine H3-receptor antagonists were prepared and their structure-activity relationship was explored. These benzimidazolone analogs demonstrate potent H3-receptor binding affinities, no P450 enzyme inhibition, and strong H3 functional activity. Compound 1o exhibits the best overall profile with H3Ki=0.95nM and rat AUC=12.9µMh.
Asunto(s)
Bencimidazoles/química , Bencimidazoles/farmacología , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacología , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Sistema Enzimático del Citocromo P-450/metabolismo , Cobayas , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Ratas , Receptores Histamínicos H3/metabolismo , Relación Estructura-ActividadRESUMEN
A novel series of non-imidazole bicyclic and tricyclic histamine H3 receptor antagonists has been discovered. Compound 17 was identified as a centrally penetrant molecule with high receptor occupancy which demonstrates robust oral activity in rodent models of obesity. In addition compound 17 possesses clean CYP and hERG profiles and shows no behavioral changes in the Irwin test.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/uso terapéutico , Obesidad/tratamiento farmacológico , Animales , Antagonistas de los Receptores Histamínicos H3/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Microsomas Hepáticos/metabolismo , Ratas , Receptores Histamínicos H3/metabolismoRESUMEN
The optimization of oxazole-based PDE4 inhibitor 1 has led to the identification of both oral (compound 16) and inhaled (compound 34) PDE4 inhibitors. Selectivity against PDE10/PDE11, off target screening, and in vivo activity in the rat are discussed.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/química , Oxazoles/química , Prolina/análogos & derivados , Quinolinas/síntesis química , Administración Oral , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4/metabolismo , Evaluación Preclínica de Medicamentos , Semivida , Inhalación , Oxazoles/síntesis química , Oxazoles/farmacocinética , Inhibidores de Fosfodiesterasa 4/síntesis química , Inhibidores de Fosfodiesterasa 4/química , Inhibidores de Fosfodiesterasa 4/farmacocinética , Prolina/síntesis química , Prolina/química , Prolina/farmacocinética , Quinolinas/química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
The structure-activity relationship studies of a novel series of carboxylic acid derivatives of pyridine-carboxamides as DGAT-1 inhibitors is described. The optimization of the initial lead compound 6 based on in vitro and in vivo activity led to the discovery of key compounds 10j and 17h.
Asunto(s)
Amidas/farmacología , Diacilglicerol O-Acetiltransferasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Animales , Diacilglicerol O-Acetiltransferasa/metabolismo , Inhibidores Enzimáticos/química , Humanos , Ratones , Relación Estructura-ActividadRESUMEN
A detailed structure-activity relationship study of a novel series of pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of the PK profile of this series led to the discovery of compound 11g, which demonstrated in vivo potency ip in a lethal fungal infection model.
Asunto(s)
Antifúngicos/química , Inhibidores Enzimáticos/química , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Sulfonamidas/química , Animales , Antifúngicos/farmacocinética , Antifúngicos/uso terapéutico , Candida/efectos de los fármacos , Candidiasis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Inhibidores Enzimáticos/uso terapéutico , Glucosiltransferasas/metabolismo , Semivida , Ratones , Pruebas de Sensibilidad Microbiana , Piridazinas/farmacocinética , Piridazinas/uso terapéutico , Ratas , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
The structure-activity relationship studies of a novel sulfonylurea series of piperazine pyridazine-based small molecule glucan synthase inhibitors is described. The optimization of PK profiles within the series led to the discovery of several compounds with improved pharmacokinetic profiles which demonstrated in vitro potency against clinically relevant strains. However, the advancement of compounds from this series into a non-lethal systemic fungal infection model failed to show in vivo efficacy.
Asunto(s)
Antifúngicos/química , Inhibidores Enzimáticos/química , Glucosiltransferasas/antagonistas & inhibidores , Plomo/química , Piperazinas/química , Piridazinas/química , Compuestos de Sulfonilurea/química , Animales , Antifúngicos/farmacología , Candida/efectos de los fármacos , Línea Celular , Inhibidores Enzimáticos/farmacología , Humanos , Estructura Molecular , Piperazina , Piridazinas/farmacología , Ratas , Relación Estructura-Actividad , Compuestos de Sulfonilurea/farmacologíaRESUMEN
A series of novel 2-piperidinopiperidine thiadiazoles were synthesized and evaluated as new leads of histamine H3 receptor antagonists. The 4-(5-([1,4'-bipiperidin]-1'-yl)-1,3,4-thiadiazol-2-yl)-2-(pyridin-2-yl)morpholine (5u) displayed excellent potency and ex vivo receptor occupancy. Compound 5u was also evaluated in vivo for antidiabetic efficacy in STZ diet-induced obesity type 2 diabetic mice for 2 or 12 days. Non-fasting glucose levels were significantly reduced as compared with vehicle-treated mice. In addition, 5u dose dependently blocked the increase of HbA1c after 12 days of treatment.
RESUMEN
The echinocandins are a class of semisynthetic natural products that target ß-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibited in vitro activity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GS in vitro, and there was a strong correlation between enzyme inhibition and in vitro antifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants of Saccharomyces cerevisiae with reduced susceptibility to the piperazinyl-pyridazinones had substitutions in FKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model of Candida glabrata infection.
Asunto(s)
Antifúngicos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Animales , Antifúngicos/química , Candida glabrata/efectos de los fármacos , Candida glabrata/enzimología , Candida glabrata/patogenicidad , Candidiasis/tratamiento farmacológico , Masculino , Ratones , Estructura Molecular , Piperazinas/química , Piperazinas/farmacología , Piridazinas/química , Piridazinas/farmacología , Saccharomyces cerevisiae/efectos de los fármacos , Saccharomyces cerevisiae/enzimologíaRESUMEN
A structure-activity relationship study of the lead 5-[4-(benzylsulfonyl)piperazin-1-yl]-4-morpholino-2-phenyl-pyridazin-3(2H)-one 1 has resulted in the identification of 2-(3,5-difluorophenyl)-4-(3-fluorocyclopentyloxy)-5-[4-(isopropylsulfonyl)piperazin-1-yl]-pyridazin-3(2H)-one 11c as a ß-1,3-glucan synthase inhibitor. Compound 11c exhibited significant efficacy in an in vivo mouse model of Candida glabrata infection.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucosiltransferasas/antagonistas & inhibidores , Piridazinas/química , Piridazinas/farmacología , Inhibidores Enzimáticos/síntesis química , Piridazinas/síntesis química , Relación Estructura-ActividadRESUMEN
We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.
Asunto(s)
Agonistas Adrenérgicos/química , Agonistas Adrenérgicos/farmacología , Compuestos de Metilurea/química , Compuestos de Metilurea/farmacología , Morfolinas/química , Morfolinas/farmacología , Actividad Motora/efectos de los fármacos , Mucosa Nasal/efectos de los fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Vena Safena/efectos de los fármacos , Agonistas Adrenérgicos/metabolismo , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Compuestos de Metilurea/metabolismo , Ratones , Ratones Endogámicos C57BL , Morfolinas/metabolismo , Actividad Motora/fisiología , Mucosa Nasal/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Recombinantes/agonistas , Proteínas Recombinantes/metabolismo , Vena Safena/metabolismo , PorcinosRESUMEN
A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed.