RESUMEN
As a part of our program to identify potent GPR40 agonists capable of being dosed orally once daily in humans, we incorporated fused heterocycles into our recently disclosed spiropiperidine and tetrahydroquinoline acid derivatives 1, 2, and 3 with the intention of lowering clearance and improving the maximum absorbable dose (Dabs). Hypothesis-driven structural modifications focused on moving away from the zwitterion-like structure. and mitigating the N-dealkylation and O-dealkylation issues led to triazolopyridine acid derivatives with unique pharmacology and superior pharmacokinetic properties. Compound 4 (LY3104607) demonstrated functional potency and glucose-dependent insulin secretion (GDIS) in primary islets from rats. Potent, efficacious, and durable dose-dependent reductions in glucose levels were seen during glucose tolerance test (GTT) studies. Low clearance, volume of distribution, and high oral bioavailability were observed in all species. The combination of enhanced pharmacology and pharmacokinetic properties supported further development of this compound as a potential glucose-lowering drug candidate.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Piridinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Triazoles/farmacología , Administración Oral , Animales , Perros , Humanos , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/síntesis química , Hipoglucemiantes/farmacocinética , Masculino , Piridinas/administración & dosificación , Piridinas/síntesis química , Piridinas/farmacocinética , Ratas , Relación Estructura-Actividad , Triazoles/administración & dosificación , Triazoles/síntesis química , Triazoles/farmacocinéticaRESUMEN
The G protein-coupled receptor 40 (GPR40) also known as free fatty acid receptor 1 (FFAR1) is highly expressed in pancreatic, islet ß-cells and responds to endogenous fatty acids, resulting in amplification of insulin secretion only in the presence of elevated glucose levels. Hypothesis driven structural modifications to endogenous FFAs, focused on breaking planarity and reducing lipophilicity, led to the identification of spiropiperidine and tetrahydroquinoline acid derivatives as GPR40 agonists with unique pharmacology, selectivity, and pharmacokinetic properties. Compounds 1 (LY2881835), 2 (LY2922083), and 3 (LY2922470) demonstrated potent, efficacious, and durable dose-dependent reductions in glucose levels along with significant increases in insulin and GLP-1 secretion during preclinical testing. A clinical study with 3 administered to subjects with T2DM provided proof of concept of 3 as a potential glucose-lowering therapy. This manuscript summarizes the scientific rationale, medicinal chemistry, preclinical, and early development data of this new class of GPR40 agonists.
Asunto(s)
Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Descubrimiento de Drogas , Hipoglucemiantes/farmacología , Piperidinas/farmacología , Receptores Acoplados a Proteínas G/agonistas , Compuestos de Espiro/farmacología , Animales , Relación Dosis-Respuesta a Droga , Prueba de Tolerancia a la Glucosa , Células HEK293 , Humanos , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Ratas , Ratas Zucker , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Relación Estructura-ActividadRESUMEN
PURPOSE: Pharmaceutical formulation and treatment process attributes, such as dose frequency and route of administration, can have an impact on quality of life, treatment adherence, and disease outcomes. The aim of this literature review was to examine studies on preferences for pharmaceutical treatment process attributes, focusing on research in diabetes, oncology, osteoporosis, and autoimmune disorders. METHODS: The literature search focused on identifying studies reporting preferences for attributes of the pharmaceutical treatment process. Studies were required to use formal quantitative preference assessment methods, such as utility valuation, conjoint analysis, or contingent valuation. Searches were conducted using Medline, EMBASE, Cochrane Library, Health Economic Evaluation Database, and National Health Service Economic Evaluation Database (January 1993-October 2013). RESULTS: A total of 42 studies met inclusion criteria: 19 diabetes, nine oncology, five osteoporosis, and nine autoimmune. Across these conditions, treatments associated with shorter treatment duration, less frequent administration, greater flexibility, and less invasive routes of administration were preferred over more burdensome or complex treatments. While efficacy and safety often had greater relative importance than treatment process, treatment process also had a quantifiable impact on preference. In some instances, particularly in diabetes and autoimmune disorders, treatment process attributes had greater relative importance than some or all efficacy and safety attributes. Some studies suggested that relative importance of treatment process depends on disease (eg, acute vs chronic) and patient (eg, injection experience) characteristics. CONCLUSION: Despite heterogeneity in study methods and design, some general patterns of preference clearly emerged. Overall, the results of this review suggest that treatment process has a quantifiable impact on preference and willingness to pay for treatment, even in many situations where safety and efficacy were the primary concerns. Patient preferences for treatment process attributes can inform drug development decisions to better meet the needs of patients and deliver improved outcomes.
RESUMEN
A transdermal SARM has a potential to have therapeutic benefit through anabolic activity in muscle while sparing undesired effects of benign prostate hyperplasia (BPH) and liver-mediated decrease in HDL-C. 2-Chloro-4-[(2-hydroxy-2-methyl-cyclopentyl)amino]-3-methyl-benzonitrile 6 showed the desired muscle and prostate effects in a preclinical ORX rat model. Compound 6 had minimal effect on HDL-C levels in cynomolgus monkeys and showed human cadaver skin permeability, thus making it an effective tool for proof-of-concept studies in a clinical setting.
Asunto(s)
Anabolizantes/uso terapéutico , Antagonistas de Andrógenos/uso terapéutico , Compuestos de Anilina/uso terapéutico , Atrofia Muscular/tratamiento farmacológico , Nitrilos/uso terapéutico , Administración Cutánea , Anabolizantes/administración & dosificación , Anabolizantes/síntesis química , Antagonistas de Andrógenos/administración & dosificación , Antagonistas de Andrógenos/síntesis química , Compuestos de Anilina/administración & dosificación , Compuestos de Anilina/síntesis química , Animales , HDL-Colesterol/metabolismo , Humanos , Hipercolesterolemia/inducido químicamente , Técnicas In Vitro , Hígado/efectos de los fármacos , Hígado/metabolismo , Macaca fascicularis , Masculino , Modelos Moleculares , Nitrilos/administración & dosificación , Nitrilos/síntesis química , Orquiectomía , Hiperplasia Prostática/inducido químicamente , Ratas , Absorción Cutánea , Relación Estructura-ActividadRESUMEN
This letter describes the discovery and SAR optimization of tetrazoyl tetrahydroquinoline derivatives as potent CETP inhibitors. Compound 6m exhibited robust HDL-c increase in hCETP/hApoA1 double transgenic model and favorable pharmacokinetic properties.
Asunto(s)
Proteínas de Transferencia de Ésteres de Colesterol/antagonistas & inhibidores , Diseño de Fármacos , Hipolipemiantes/síntesis química , Quinolinas/química , Tetrazoles/síntesis química , Animales , Apolipoproteína A-I/genética , Apolipoproteína A-I/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/genética , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , HDL-Colesterol/efectos de los fármacos , HDL-Colesterol/metabolismo , Perros , Femenino , Hipolipemiantes/química , Hipolipemiantes/farmacocinética , Inyecciones Intravenosas , Masculino , Ratones , Ratones Transgénicos , Quinolinas/síntesis química , Quinolinas/farmacocinética , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Tetrazoles/química , Tetrazoles/farmacocinéticaRESUMEN
This Letter describes the discovery and SAR optimization of 1,5-tetrahydronaphthyridines, a new class of potent CETP inhibitors. The effort led to the identification of 21b and 21d with in vitro human plasma CETP inhibitory activity in the nanomolar range (IC(50)=23 and 22nM, respectively). Both 21b and 21d exhibited robust HDL-c increase in hCETP/hApoA1 dual heterozygous mice model.