RESUMEN
We identified (5R)-6-methyl-5-phenyl-1,3,4,5,6,7-hexahydro-2,5-methano-2,6-benzodiazonine (DS21980956: 4-(R)) as a novel [5.2.1]bicyclic basic compound. The scaffold was inspired by fentanyl or pethidine, which possess potent analgesic activities. DS21980956 had potent analgesic activity in the mouse acetic acid writhing test or tail flick test without agonistic activity at the µ opioid receptor (MOR). The mechanism of analgesic action of DS21980956 was considered to differ from a biased ligand, for example, TRV-130 (3, oliceridine).
Asunto(s)
Aminas/uso terapéutico , Analgésicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Dolor/tratamiento farmacológico , Ácido Acético , Aminas/química , Analgésicos/química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Relación Dosis-Respuesta a Droga , Ratones , Ratones Endogámicos , Estructura Molecular , Dolor/inducido químicamente , Dimensión del Dolor , Relación Estructura-ActividadRESUMEN
Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.
Asunto(s)
Fármacos Antiobesidad/química , Fármacos Antiobesidad/farmacología , Azepinas/química , Azepinas/farmacología , Receptores de Bombesina/agonistas , Animales , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Azepinas/síntesis química , Azepinas/farmacocinética , Perros , Evaluación de Medicamentos , Humanos , Ratones , Modelos Moleculares , Conformación Molecular , Obesidad/tratamiento farmacológico , Obesidad/metabolismo , Ratas , Relación Estructura-ActividadRESUMEN
The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.
Asunto(s)
Azepinas/síntesis química , Barrera Hematoencefálica , Receptores de Bombesina/agonistas , Animales , Azepinas/metabolismo , Azepinas/farmacología , Encéfalo/efectos de los fármacos , Células Cultivadas , Humanos , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P1', P2' and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys.
Asunto(s)
Amidas/química , Piperazinas/síntesis química , Piperidinas/química , Piperidinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Amidas/farmacocinética , Amidas/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Furosemida/farmacología , Semivida , Hipertensión/tratamiento farmacológico , Macaca fascicularis , Piperazinas/farmacocinética , Piperazinas/uso terapéutico , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/uso terapéutico , Ratas , Ratas Transgénicas , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.
Asunto(s)
Antihipertensivos/síntesis química , Arritmias Cardíacas/prevención & control , Corazón/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Piperazinas/síntesis química , Inhibidores de Proteasas/síntesis química , Renina/antagonistas & inhibidores , Administración Oral , Animales , Antihipertensivos/farmacocinética , Antihipertensivos/farmacología , Presión Arterial/efectos de los fármacos , Femenino , Corazón/fisiopatología , Humanos , Hipertensión/enzimología , Hipertensión/fisiopatología , Macaca fascicularis , Masculino , Técnicas de Cultivo de Órganos , Piperazinas/farmacocinética , Piperazinas/farmacología , Inhibidores de Proteasas/farmacocinética , Inhibidores de Proteasas/farmacología , Conejos , Ratas , Renina/química , Renina/metabolismo , Relación Estructura-ActividadAsunto(s)
Inhibidores Enzimáticos/síntesis química , Alcaloides de Pirrolicidina/síntesis química , Acremonium/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Compuestos Aza/química , Reacción de Cicloadición , Inhibidores Enzimáticos/química , Alcaloides de Pirrolicidina/química , Estereoisomerismo , Telomerasa/antagonistas & inhibidores , Telomerasa/metabolismoRESUMEN
A practical deoxyfluorination with novel deoxyfluorinating reagent PhenoFluorMix, a mixture of N,N'-1,3-bis(2,6-diisopropylphenyl)chloroimidazolium chloride and CsF, is presented. PhenoFluorMix overcomes the challenges associated with hydrolysis of PhenoFluor. PhenoFluorMix does not hydrolyze, is readily available on decagram scale, and is storable in air. In this paper, we demonstrate the practicality of the reagent and exhibit the deoxyfluorination of a variety of phenols and heterocycles.
RESUMEN
A total synthesis of the potent immunosuppressant FR901483 (1) has been accomplished. The key feature of our convergent synthesis is the stereoselective incorporation of the p-methoxybenzyl and methylamino groups within the core moiety 10. Tricycle 10 was itself constructed by an intramolecular aldol reaction of the symmetrical keto-aldehyde 7. [Structure: see text]
Asunto(s)
Inmunosupresores/síntesis química , Compuestos Organofosforados/síntesis química , Aldehídos/química , Alquilación , Ascomicetos , Metilaminas/químicaRESUMEN
We report a practical synthesis method of the reagent PhenoFluor on decagram scale, provide a new formulation of PhenoFluor as a toluene solution, which should decrease challenges associated with the moisture sensitivity of the reagent, and expand the substrate scope of deoxyfluorination with PhenoFluor to heteroaromatics.
RESUMEN
A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.