RESUMEN
Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.
Asunto(s)
Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/química , Piperidinas/química , Pirrolidinas/química , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Inhibidores de la Dipeptidil-Peptidasa IV/metabolismo , Humanos , Concentración de Iones de Hidrógeno , Unión Proteica , Pirrolidinas/síntesis química , Pirrolidinas/metabolismo , Relación Estructura-Actividad , TemperaturaRESUMEN
Inhibition of sodium-dependent glucose transporter 2 (SGLT2), the transporter that is responsible for renal re-uptake of glucose, leads to glucosuria in animals. SGLT-mediated glucosuria provides a mechanism to shed excess plasma glucose to ameliorate diabetes-related hyperglycemia and associated complications. The current study demonstrates that the proper relationship of a 4'-substituted benzyl group to a beta-1C-phenylglucoside is important for potent and selective SGLT2 inhibition. The lead C-arylglucoside (7a) demonstrates superior metabolic stability to its O-arylglucoside counterpart (4) and it promotes glucosuria when administered in vivo.
Asunto(s)
Glucósidos/química , Glucósidos/farmacología , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Animales , Glucosa/química , Glucosuria Renal/tratamiento farmacológico , Humanos , Riñón/efectos de los fármacos , Ratas , Transportador 1 de Sodio-Glucosa/antagonistas & inhibidores , Transportador 2 de Sodio-GlucosaRESUMEN
The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glucósidos/síntesis química , Hipoglucemiantes/síntesis química , Riñón/metabolismo , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Administración Oral , Animales , Compuestos de Bencidrilo , Glucemia/metabolismo , Diabetes Mellitus Experimental/tratamiento farmacológico , Glucósidos/química , Glucósidos/farmacología , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/farmacología , Ratas , Transportador 2 de Sodio-Glucosa , EstereoisomerismoRESUMEN
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
Enzymes catalyze multistep chemical reactions and achieve phenomenal rate accelerations by matching protein and substrate chemical groups in the transition state. Inhibitors that take advantage of these chemical interactions are among the most potent and effective drugs known. Recently, three new enzyme targets have been validated by FDA approval of new enzyme inhibitor drugs. These include mitogen-activated protein kinase, renin, and dipeptidyl peptidase IV. The drugs against these enzymes engage important enzyme functional groups, such as the active site serine in dipeptidyl peptidase IV. Clinical and pre-clinical discovery programs also demonstrate the same theme, as evidenced by pM and fM transition state inhibitors of purine nucleoside phosphorylase, methylthioadenosine phosphorylase, and 5-methylthioadenosine/S-adenosylhomocysteine nucleosidase, and covalent substrate trapping in leu-tRNA synthetase. The catalytic chemistry of enzymes is the key to designing potent inhibitors and makes them a special class of drug target.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Enzimas/efectos de los fármacos , Aprobación de Drogas , Inhibidores Enzimáticos/uso terapéutico , Humanos , Especificidad por SustratoRESUMEN
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
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
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
Enzymes offer unique opportunities for drug design that are not available to cell surface receptors, nuclear hormone receptors, ion channels, transporters, and DNA. Here, we review the variety of inhibition mechanisms for enzyme-targeted drugs, and establish an enzyme target database for drugs currently marketed in the United States. From an analysis of the FDA Orange Book, there are 317 marketed drugs that work by inhibiting an enzyme. These drugs inhibit 71 enzymes, including 48 human, 13 bacterial, five viral, four fungal, and one protozoal enzyme. Among the 317 drugs, 65% either undergo reactive chemistry in the active site of the target enzyme or contain a structural motif related to the substrate. Among the 71 enzyme targets, 25 are irreversibly inhibited by drugs, and 19 of the 25 irreversibly inhibited enzymes are covalently modified by the drug. In two additional cases, the drug forms a covalent complex with the substrate, and in three more cases, the drug traps a covalent enzyme-substrate intermediate. Four of the 71 enzymes are inhibited by transition-state analogues. Moreover, advanced methods for determining transition-state structure now offer the opportunity for direct drug design without resorting to expensive random testing campaigns. A full appreciation of enzyme mechanisms sets enzymes apart as a specialized class of targets for highly directed drug design.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Enzimas/efectos de los fármacos , Enzimas/metabolismo , Animales , Bases de Datos Factuales , Diseño de Fármacos , Activación Enzimática/efectos de los fármacos , Humanos , Estructura Molecular , Especificidad por SustratoRESUMEN
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
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.