RESUMEN
Using a function-oriented synthesis strategy, we designed, synthesized, and evaluated the simplest bryostatin 1 analogues reported to date, in which bryostatin's A- and B-rings are replaced by a glutarate linker. These analogues, one without and one with a C26-methyl group, exhibit remarkably different protein kinase C (PKC) isoform affinities. The former exhibited bryostatin-like binding to several PKC isoforms with Ki's < 5 nM, while the latter exhibited PKC affinities that were up to â¼180-fold less potent. The analogue with bryostatin-like PKC affinities also exhibited bryostatin-like PKC translocation kinetics in vitro, indicating rapid cell permeation and engagement of its PKC target. This study exemplifies the power of function-oriented synthesis in reducing structural complexity by activity-informed design, thus enhancing synthetic accessibility, while still maintaining function (biological activity), collectively providing new leads for addressing the growing list of therapeutic indications exhibited by PKC modulators.
Asunto(s)
Macrólidos , Proteína Quinasa C , Brioestatinas/farmacología , LactonasRESUMEN
Novel thienopyrimidine compounds 2 and 3 were discovered from high-throughput screening as Natriuretic Peptide Receptor A (NPR-A) agonists. Scaffold hopping of a thienopyrimidine ring to a quinazoline ring, introduction of the basic functional group and optimization of the substituent on the 6-position of the benzene ring of quinazoline led to improved agonistic activity. We discovered compound 48, which showed potent agonistic activity for NPR-A with an EC50 value of 0.073µM, indicating 350-fold potency compared to the hit compound 3.
Asunto(s)
Pirimidinas/metabolismo , Receptores del Factor Natriurético Atrial/agonistas , Animales , Células CHO , Cricetinae , Cricetulus , Evaluación Preclínica de Medicamentos , Humanos , Pirimidinas/síntesis química , Pirimidinas/química , Quinazolinas/síntesis química , Quinazolinas/química , Quinazolinas/metabolismo , Receptores del Factor Natriurético Atrial/metabolismo , Relación Estructura-ActividadRESUMEN
The Prins cyclization of syn-ß-hydroxy allylsilanes and aldehydes gives cis-2,6-disubstituted 4-alkylidenetetrahydropyrans as sole products in excellent yields regardless of the aldehyde (Râ³) or syn-ß-hydroxy allylsilane substituent (R') used. By reversing the Râ³ and R' groups, complementary exocyclic stereocontrol can be achieved. When the anti-ß-hydroxy allylsilanes are used, the Prins cyclization gives predominantly cis-2,6-disubstituted 4-alkylidenetetrahydropyrans, now with the opposite olefin geometry in excellent yield. The proposed reaction mechanism and the observed stereoselectivity for these processes are supported by DFT calculations.
Asunto(s)
Alquenos/síntesis química , Brioestatinas/síntesis química , Piranos/síntesis química , Alquenos/química , Brioestatinas/química , Ciclización , Estructura Molecular , Piranos/química , EstereoisomerismoRESUMEN
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-ActividadRESUMEN
Utilizing X-ray crystal structure analysis, (3S,5R)-5-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]piperidine-3-carboxamides were designed and identified as renin inhibitors. The most potent compound 15 demonstrated favorable pharmacokinetic and pharmacodynamic profiles in rat.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Descubrimiento de Drogas , Piperazinas/farmacología , Piperidinas/farmacología , Renina/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/síntesis química , Inhibidores de la Enzima Convertidora de Angiotensina/química , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Haplorrinos , Humanos , Modelos Moleculares , Conformación Molecular , Piperazinas/síntesis química , Piperazinas/química , Piperidinas/síntesis química , Piperidinas/química , Renina/sangre , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
The absolute configuration was determined for the title compound, (-)-C(32)H(56)O(6)S(2)Si, (I), which was prepared in a synthetic study on the natural products bryostatins. Two independent molecules show similar conformations, except for the orientation of the methoxy groups.
RESUMEN
The absolute configuration was determined for the title compound, (+)-C(18)H(24)O(3)S, (I), which was prepared in a synthetic study on the natural products, bryostatins.
RESUMEN
GPR142 is a G protein-coupled receptor that is predominantly expressed in pancreatic ß-cells. GPR142 agonists stimulate insulin secretion in the presence of high glucose concentration, so that they could be novel insulin secretagogues with reduced or no risk of hypoglycemia. We report here the optimization of HTS hit compound 1 toward a proof of concept compound 33, which showed potent glucose lowering effects during an oral glucose tolerance test in mice and monkeys.
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.