RESUMEN
The synthesis and structure-activity relationships of novel dipeptidyl peptidase IV inhibitors replacing the classical cyanopyrrolidine P1 group with other small nitrogen heterocycles are described. A unique potency enhancement was achieved with beta-branched natural and unnatural amino acids, particularly adamantylglycines, linked to a (2S,3R)-2,3-methanopyrrolidine based scaffold.
Asunto(s)
Dipéptidos/química , Inhibidores de la Dipeptidil-Peptidasa IV , Inhibidores de la Dipeptidil-Peptidasa IV/química , Dipéptidos/farmacología , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Nitrilos/química , Nitrilos/farmacología , Relación Estructura-ActividadRESUMEN
The NMR structure is presented for compound 1 (BMS-480404) (Ki = 33 (+/-2) nM) bound to keratinocyte fatty acid-binding protein. This article describes interactions between a high affinity drug-like compound and a member of the fatty acid-binding protein family. A benzyl group ortho to the mandelic acid in 1 occupies an area of the protein that fatty acids do not normally contact. Similar to that in the kFABP-palmitic acid structure, the acid moiety in 1 is proximal to R129 and Y131. Computational modeling indicates that the acid moiety in 1 interacts indirectly via a modeled water molecule to R109.
Asunto(s)
Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/química , Queratinocitos/metabolismo , Sitios de Unión , Simulación por Computador , Proteínas de Unión a Ácidos Grasos/metabolismo , Humanos , Ligandos , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Estructura MolecularRESUMEN
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
Asunto(s)
Adamantano/análogos & derivados , Adamantano/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipéptidos/síntesis química , Dipeptidil Peptidasa 4/metabolismo , Glicina/análogos & derivados , Glicina/síntesis química , Hipoglucemiantes/síntesis química , Inhibidores de Proteasas/síntesis química , Adamantano/farmacología , Animales , Disponibilidad Biológica , Glucemia/análisis , Diabetes Mellitus Tipo 2/fisiopatología , Dipéptidos/farmacología , Prueba de Tolerancia a la Glucosa , Glicina/farmacología , Humanos , Hipoglucemiantes/farmacología , Técnicas In Vitro , Insulina/sangre , Masculino , Ratones , Ratones Obesos , Microsomas Hepáticos/metabolismo , Nitrilos/síntesis química , Nitrilos/farmacología , Prolina/análogos & derivados , Prolina/síntesis química , Prolina/farmacología , Inhibidores de Proteasas/farmacología , Ratas , Ratas Zucker , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of methanoprolinenitrile-containing dipeptide mimetics were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV (DPP-IV). The catalytic action of DPP-IV is the principle means of degradation of glucagon-like peptide-1, a key mediator of glucose-stimulated insulin secretion, and DPP-IV inhibition shows clinical benefit as a novel mechanism for treatment of type 2 diabetes. However, many of the reversible inhibitors to date suffer from chemical instability stemming from an amine to nitrile intramolecular cyclization. Installation of a cyclopropyl moiety at either the 3,4- or 4,5-position of traditional 2-cyanopyrrolidide proline mimetics led to compounds with potent inhibitory activity against the enzyme. Additionally, cis-4,5-methanoprolinenitriles with beta-branching in the N-terminal amino acid provided enhanced chemical stability and high inhibitory potency. This class of inhibitors also exhibited the ability to suppress prandial glucose elevations after an oral glucose challenge in male Zucker rats.
Asunto(s)
Ciclopropanos/síntesis química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores Enzimáticos/síntesis química , Nitrilos/síntesis química , Prolina/análogos & derivados , Prolina/síntesis química , Animales , Simulación por Computador , Cristalografía por Rayos X , Ciclopropanos/química , Ciclopropanos/farmacología , Dipéptidos/química , Dipeptidil Peptidasa 4/química , Estabilidad de Medicamentos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Hipoglucemiantes/síntesis química , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Masculino , Modelos Moleculares , Conformación Molecular , Imitación Molecular , Nitrilos/química , Nitrilos/farmacología , Prolina/química , Prolina/farmacología , Ratas , Ratas Zucker , SolucionesRESUMEN
[reaction: see text] 1-Aminonaphthalenes and 5- and 8-aminoquinolines were rapidly prepared from the respective aryl bromides in good yields by Pd-catalyzed aryl amination under microwave conditions. Consistent improvements in yields over those obtained under standard conditions were seen with quinoline substrates. In the cases where 5-bromo-8-cyanoquinoline was used as a substrate, no desired products were obtained under standard conditions with a number of different primary and secondary amines. However, microwave conditions provided the desired products in good to excellent yields.
RESUMEN
Herein we report the first disclosure of biphenyl azoles that are nanomolar binders of adipocyte fatty acid binding protein (aFABP or aP2) with up to thousand-fold selectivity against muscle fatty acid binding protein and epidermal fatty acid binding protein. In addition a new radio-ligand to determine binding against the three fatty acid binding proteins was also synthesized.
Asunto(s)
Adipocitos/efectos de los fármacos , Azoles/antagonistas & inhibidores , Compuestos de Bifenilo/antagonistas & inhibidores , Proteínas de Unión a Ácidos Grasos/antagonistas & inhibidores , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Adipocitos/metabolismo , Animales , Sitios de Unión , Modelos Animales de Enfermedad , Epidermis/metabolismo , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Ratones , Modelos Químicos , Ensayo de Unión RadioliganteRESUMEN
A series of seco-prolinenitrile-containing dipeptides were synthesized and assayed as inhibitors of the N-terminal sequence-specific serine protease dipeptidyl peptidase IV, a promising new target for treatment of type 2 diabetes. The inhibitors described herein assess the minimum structural requirements at P1 for this enzyme, resulting in the identification of inhibitors with low nM potency.
Asunto(s)
Adenosina Desaminasa/química , Dipéptidos , Dipeptidil Peptidasa 4/química , Inhibidores Enzimáticos , Glicoproteínas/química , Nitrilos , Prolina/química , Compuestos de Anilina/metabolismo , Dipéptidos/síntesis química , Dipéptidos/química , Dipéptidos/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Nitrilos/síntesis química , Nitrilos/química , Nitrilos/farmacologíaRESUMEN
Dipeptidyl peptidase IV (DPP4) is a multifunctional type II transmembrane serine peptidase which regulates various physiological processes, most notably plasma glucose homeostasis by cleaving peptide hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide. Inhibition of DPP4 is a potentially valuable therapy for type 2 diabetes. Synthesis and structure-activity relationships of a series of substituted diprolyl nitriles are described, leading to the identification of compound 1 with a measured DPP4 K(i) of 3.6 nM.
Asunto(s)
Dipeptidil Peptidasa 4/metabolismo , Nitrilos/farmacología , Inhibidores de Proteasas/farmacología , Sitios de Unión , Ciclización , Dipeptidil Peptidasa 4/química , Modelos Moleculares , Estructura Molecular , Nitrilos/química , Inhibidores de Proteasas/química , Estructura Terciaria de ProteínaRESUMEN
Using available commercial robotics and instrumentation, we developed a fully automated and rigorous steady state enzyme kinetic assay for dipeptidyl peptidase IV (DPP IV; E.C. 3.4.14.5). The automated assay was validated with isoleucyl thiazolidide, a potent inhibitor of DPP IV with K(is)=110nM. Signal window analysis indicated that the assay had a 98% probability of detecting an inhibitor yielding 15% inhibition, with a predicted false positive rate of 0.13%. A mechanistic inhibition version of the automated assay was validated with isoleucyl 4-cyanothiazolidide, a very potent inhibitor of DPP IV. Isoleucyl 4-cyanothiazolidide was a competitive inhibitor of purified porcine DPP IV with K(is)=1 nM. Similar K(is) values were obtained for purified rat DPP IV and for DPP IV activity in human plasma from normal and diabetic donors. The pH dependence of K(is) for isoleucyl 4-cyanothiazolidide yielded a bell-shaped profile, with pK(a)=5.0 and pK(b)=7.6. To date, over 100,000 data points have been generated in profiling targeted compound libraries and in the analysis of tight-binding inhibitors of DPP IV. The data also show that robotic analysis is capable of producing full mechanistic inhibition analysis in a timely fashion to support drug discovery.
Asunto(s)
Dipeptidil Peptidasa 4/análisis , Isoleucina/análogos & derivados , Inhibidores de Proteasas/farmacología , Robótica/métodos , Animales , Unión Competitiva , Dipeptidil Peptidasa 4/sangre , Dipeptidil Peptidasa 4/metabolismo , Humanos , Isoleucina/metabolismo , Isoleucina/farmacología , Riñón/enzimología , Cinética , Modelos Químicos , Inhibidores de Proteasas/metabolismo , Ratas , Tiazoles/metabolismo , Tiazoles/farmacologíaRESUMEN
A series of newly synthesized phosphonate esters were evaluated for their effects on microsomal triglyceride transfer protein activity (MTP). The most potent compounds were evaluated for their ability to inhibit lipoprotein secretion in HepG2 cells and to affect VLDL secretion in rats. These inhibitors were also found to lower serum cholesterol levels in a hamster model upon oral dosing.