RESUMEN
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.
RESUMEN
The design, synthesis, SAR, and biological profile of a substituted 4-morpholine sulfonamide series of γ-secretase inhibitors (GSIs) were described. In several cases, the resulting series of GSIs reduced CYP liabilities and improved γ-secretase inhibition activity compared to our previous research series. Selected compounds demonstrated significant reduction of amyloid-ß (Aß) after acute oral dosing in a transgenic animal model of Alzheimer's disease (AD).
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Morfolinas/química , Morfolinas/farmacología , Sulfonamidas/química , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores Enzimáticos/uso terapéutico , Femenino , Masculino , Ratones , Morfolinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
We have been focused on identifying a structurally different next generation inhibitor to MK-5172 (our Ns3/4a protease inhibitor currently under regulatory review), which would achieve superior pangenotypic activity with acceptable safety and pharmacokinetic profile. These efforts have led to the discovery of a novel class of HCV NS3/4a protease inhibitors containing a unique spirocyclic-proline structural motif. The design strategy involved a molecular-modeling based approach, and the optimization efforts on the series to obtain pan-genotypic coverage with good exposures on oral dosing. One of the key elements in this effort was the spirocyclization of the P2 quinoline group, which rigidified and constrained the binding conformation to provide a novel core. A second focus of the team was also to improve the activity against genotype 3a and the key mutant variants of genotype 1b. The rational application of structural chemistry with molecular modeling guided the design and optimization of the structure-activity relationships have resulted in the identification of the clinical candidate MK-8831 with excellent pan-genotypic activity and safety profile.
RESUMEN
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Iminas/farmacología , Pirimidinonas/farmacología , Renina/antagonistas & inhibidores , Administración Oral , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Iminas/síntesis química , Iminas/química , Modelos Moleculares , Estructura Molecular , Pirimidinonas/síntesis química , Pirimidinonas/química , Renina/metabolismo , Relación Estructura-ActividadRESUMEN
An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective γ-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF(3) and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Benzopiranos/síntesis química , Benzopiranos/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Sulfonas/síntesis química , Sulfonas/farmacología , Benzopiranos/química , Ciclización , Activación Enzimática/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piranos/síntesis química , Piranos/química , Piranos/farmacología , Relación Estructura-Actividad , Sulfonas/químicaRESUMEN
An exploration of the SAR of the side chain of a novel tricyclic series of γ-secretase inhibitors led to the identification of compound (-)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aß40 IC50 = 1.3 nM). Compound (-)-16 demonstrated excellent lowering of Aß after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer's disease.
RESUMEN
A novel series of tricyclic gamma-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous gamma-secretase inhibitors.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Receptores Notch/efectos de los fármacos , Sulfonas/química , Sulfonas/farmacología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Ratones , Modelos Moleculares , Sulfonas/síntesis químicaRESUMEN
A new class of 2,6-disubstituted morpholine N-arylsulfonamide gamma-secretase inhibitors was designed based on the introduction of a morpholine core in lieu or piperidine in our lead series. This resulted in compounds with improved CYP 3A4 profiles. Several analogs that were active at lowering Abeta levels in Tg CRND8 mice upon oral administration were identified.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos/química , Morfolinas/química , Sulfonamidas/química , Administración Oral , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Animales , Citocromo P-450 CYP3A/metabolismo , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Humanos , Ratones , Ratones Transgénicos , Morfolinas/síntesis química , Morfolinas/farmacocinética , Ratas , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinéticaRESUMEN
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Piperidinas/síntesis química , Piperidinas/farmacología , Sulfonamidas/síntesis química , Sulfonamidas/farmacología , Administración Oral , Péptidos beta-Amiloides/biosíntesis , Animales , Área Bajo la Curva , Sistema Enzimático del Citocromo P-450/metabolismo , Diseño de Fármacos , Espectroscopía de Resonancia Magnética , Ratones , Conformación Molecular , Peso Molecular , Oxidorreductasas/metabolismoRESUMEN
Development of cis-2,4,6-trisubstituted piperidine N-arylsulfonamides as gamma-secretase inhibitors for the potential treatment of Alzheimer's disease (AD) is reported.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Piperidinas/síntesis química , Piperidinas/farmacología , Citocromo P-450 CYP3A/efectos de los fármacos , Inhibidores Enzimáticos/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piperidinas/química , Relación Estructura-Actividad , Sulfonamidas/químicaRESUMEN
Attachment of the cyclopropylcarbamate group to the piperidine core of gamma-secretase inhibitors leads to a dramatic increase of their in vitro potency. Strategies for subsequent improvement of the in vivo pharmacokinetic profile of the series are discussed. Resulting compounds significantly reduce Abeta levels in TgCRND8 mice after a single PO dosing at 30 mpk.