RESUMEN
Inhibition of 11ß-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzoatos/farmacología , Inhibidores Enzimáticos/farmacología , Glucurónidos/metabolismo , Pirazoles/química , Pirazoles/farmacología , Piridinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Tejido Adiposo/efectos de los fármacos , Tejido Adiposo/enzimología , Animales , Benzoatos/síntesis química , Benzoatos/farmacocinética , Perros , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Glucurónidos/química , Cobayas , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Macaca fascicularis , Ratones , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Pirazoles/síntesis química , Pirazoles/farmacocinética , Ratas , Ratas Wistar , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
11ß-HSD1 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. In this program of work we describe how a series of neutral 2-thioalkyl-pyridine 11ß-HSD1 inhibitors were optimized in terms of their pharmacokinetic properties to give compounds with excellent bioavailability in both rat and dog through a core change to pyrimidine. A potential reactive metabolite issue with 4-thioalkyl-pyrimidines was circumvented by a switch from sulfur to carbon substitution.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacocinética , Piridinas/química , Compuestos de Sulfhidrilo/química , Animales , Perros , Inhibidores Enzimáticos/química , Concentración 50 Inhibidora , Estructura Molecular , Piridinas/farmacocinética , Ratas , Compuestos de Sulfhidrilo/farmacocinéticaRESUMEN
Inhibition of 11ß-HSD1 is an attractive mechanism for the treatment of obesity and other elements of the metabolic syndrome. We report here the discovery of a nicotinic amide derived carboxylic acid class of inhibitors that has good potency, selectivity, and pharmacokinetic characteristics. Compound 11i (AZD4017) is an effective inhibitor of 11ß-HSD1 in human adipocytes and exhibits good druglike properties and as a consequence was selected for clinical development.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/farmacocinética , Niacinamida/análogos & derivados , Piperidinas/farmacología , Piperidinas/farmacocinética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Disponibilidad Biológica , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/metabolismo , Humanos , Concentración 50 Inhibidora , Masculino , Ratones , Modelos Moleculares , Niacinamida/administración & dosificación , Niacinamida/metabolismo , Niacinamida/farmacocinética , Niacinamida/farmacología , Piperidinas/administración & dosificación , Piperidinas/metabolismo , Conformación Proteica , Ratas , Especificidad por SustratoRESUMEN
The displacement of probes that bind selectively to subdomains IIA or IIIA on human serum albumin (HSA) by competing compounds has been followed using fluorescence spectroscopy, and has therefore been used to assign a primary binding site for these compounds in the presence and absence of fatty acids. The crystal structures have also been solved for three compounds: a matched pair of carboxylic acids whose binding strength to HSA unexpectedly decreased as the lipophilicity increased; and a highly bound sulphonamide that appeared not to displace the probes in the displacement assay. The crystallography results support the findings from the fluorescence displacement assay. The results indicate that drug binding to subdomain IB might also be important location for certain compounds.
Asunto(s)
Preparaciones Farmacéuticas/química , Albúmina Sérica/química , Sitios de Unión , Cristalografía por Rayos X , Interacciones Farmacológicas , Humanos , Unión Proteica , Estructura Terciaria de Proteína , Albúmina Sérica/metabolismo , Espectrometría de FluorescenciaRESUMEN
A series of carboxylic acid glycogen phosphorylase inhibitors, which have potential as oral antidiabetic agents, is described. Defining and applying simple physicochemical design criteria was used to assess the opportunity and to focus synthetic efforts on compounds with the greatest probability of success. The study led to compound 17, which exhibits a good balance of properties including potent inhibition of recombinant human liver glycogen phosphorylase in vitro, a good DMPK profile including excellent bioavailability and low clearance and good in vivo activity in a glucagon challenge model of diabetes in Zucker rats.
Asunto(s)
Ácidos Carboxílicos/farmacología , Glucógeno Fosforilasa de Forma Hepática/antagonistas & inhibidores , Hipoglucemiantes/química , Indanos/farmacología , Animales , Disponibilidad Biológica , Ácidos Carboxílicos/química , Ácidos Carboxílicos/uso terapéutico , Descubrimiento de Drogas , Humanos , Hipoglucemiantes/farmacología , Indanos/química , Indanos/uso terapéutico , Ratas , Ratas ZuckerRESUMEN
The pharmaceutical industry, particularly the small molecule domain, faces unprecedented challenges of escalating costs, high attrition as well as increasing competitive pressure from other companies and from new treatment modes such as biological products. In other industries, process improvement approaches, such as Lean Sigma, have delivered benefits in speed, quality and cost of delivery. Examining the medicinal chemistry contributions to the iterative improvement process of design-make-test-analyse from a Lean Sigma perspective revealed that major improvements could be made. Thus, the cycle times of synthesis, as well as compound analysis and purification, were reduced dramatically. Improvements focused on team, rather than individual, performance. These new ways of working have consequences for staff engagement, goals, rewards and motivation, which are also discussed.
Asunto(s)
Química Farmacéutica/métodos , Química Farmacéutica/normas , Animales , Química Farmacéutica/tendencias , Humanos , Preparaciones Farmacéuticas/síntesis química , Preparaciones Farmacéuticas/normas , Control de Calidad , Factores de TiempoRESUMEN
Matched molecular pair analysis has been used in design of inhibitors of glycogen phosphorylase.
Asunto(s)
Química Farmacéutica/métodos , Glucógeno Fosforilasa/antagonistas & inhibidores , Carbono/química , Ácidos Carboxílicos/química , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/química , Concentración 50 Inhibidora , Metilación , Modelos Químicos , Análisis Multivariante , Nitrógeno/química , Relación Estructura-Actividad Cuantitativa , Solubilidad , Tetrazoles/química , Agua/químicaRESUMEN
A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Glucógeno Fosforilasa/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Quinolinas/síntesis química , Quinolinas/farmacología , Animales , Disponibilidad Biológica , Proteínas Sanguíneas/metabolismo , Células CACO-2 , Fenómenos Químicos , Química Física , Cristalografía por Rayos X , Hepatocitos/efectos de los fármacos , Hepatocitos/enzimología , Humanos , Indicadores y Reactivos , Hígado/enzimología , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Conformación Molecular , Músculo Esquelético/enzimología , Conejos , RatasRESUMEN
Two series of novel thienopyrrole inhibitors of recombinant human liver glycogen phosphorylase a (GPa) which are effective in reducing glucose output from rat hepatocytes are described. Representative compounds have been shown to bind at the dimer interface site of the rabbit muscle enzyme by X-ray crystallography.