RESUMEN
The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK-GKRP disrupters are revealed. Diarylmethanesulfonamide hit 6 (hGK-hGKRP IC50 = 1.2 µM) was optimized to lead compound 32 (AMG-0696; hGK-hGKRP IC50 = 0.0038 µM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (nN â σ*S-X) in 32 was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound 32 was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = -45%; 100 mg/kg po, 3 h). X-ray analyses of 32 and several precursors bound to GKRP were also obtained. This novel disrupter of GK-GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glucoquinasa/metabolismo , Hipoglucemiantes/química , Sulfonamidas/química , Tiofenos/química , Transporte Activo de Núcleo Celular , Animales , Glucemia/metabolismo , Núcleo Celular/metabolismo , Cristalografía por Rayos X , Citoplasma/metabolismo , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Masculino , Ratones , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Conformación Molecular , Unión Proteica , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacología , Tiofenos/farmacocinética , Tiofenos/farmacologíaRESUMEN
In a series of bradykinin B1 antagonists, we discovered that replacement of oxopiperazine acetamides with dehydro-oxopiperazine acetamides provided compounds with enhanced activity against the B1 receptor. The synthesis and SAR leading to potent analogs with reduced molecular weight will be discussed.
Asunto(s)
Acetamidas/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Piperazinas/farmacología , Acetamidas/síntesis química , Acetamidas/química , Relación Dosis-Respuesta a Droga , Humanos , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The discovery of novel and highly potent oxopiperazine based B1 receptor antagonists is described. Compared to the previously described arylsulfonylated (R)-3-amino-3-phenylpropionic acid series, the current compounds showed improved in vitro potency and metabolic stability. Compound 17, 2-((2R)-1-((4-methylphenyl)sulfonyl)-3-oxo-2-piperazinyl)-N-((1R)-6-(1-piperidinylmethyl)-1,2,3,4-tetrahydro-1-naphthalenyl)acetamide, showed EC(50) of 10.3 nM in a rabbit biochemical challenge model. The practical syntheses of chiral arylsulfonylated oxopiperazine acetic acids are also described.
Asunto(s)
Acetamidas/uso terapéutico , Antagonistas del Receptor de Bradiquinina B1 , Inflamación/tratamiento farmacológico , Dolor/tratamiento farmacológico , Piperazinas/uso terapéutico , Acetamidas/síntesis química , Acetamidas/química , Animales , Perros , Concentración 50 Inhibidora , Ratones , Modelos Animales , Estructura Molecular , Piperazinas/síntesis química , Piperazinas/química , Conejos , Ratas , Receptor de Bradiquinina B1/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Intracellular levels of the hypoxia-inducible transcription factor (HIF) are regulated under normoxic conditions by prolyl hydroxylases (PHD1, 2, and 3). Treatment of cells with PHD inhibitors stabilizes HIF-1α, eliciting an artificial hypoxic response that includes the transcription of genes involved in erythropoiesis, angiogenesis, and glycolysis. The different in vivo roles of the three PHD isoforms are not yet known, making a PHD-selective inhibitor useful as a biological tool. Although several chemical series of PHD inhibitors have been described, significant isoform selectivity has not been reported. Here we report the synthesis and activity of dipeptidyl analogues derived from a potent but non-selective quinolone scaffold. The compounds were prepared by Pd-catalyzed reductive carbonylation of the 6-iodoquinolone derivative to form the aldehyde directly, which was then attached to a solid support via reductive amination. Amino acids were coupled, and the resulting dipeptidyl-quinolone derivatives were screened, revealing retention of PHD inhibitory activity but an altered PHD1, 2, and 3 selectivity profile. The compounds were found to be â¼10-fold more potent against PHD1 and PHD3 than against PHD2, whereas the specific parent compound had shown no appreciable selectivity among the different PHD isoforms.
Asunto(s)
Dipéptidos/farmacología , Inhibidores Enzimáticos/farmacología , Isoenzimas/antagonistas & inhibidores , Procolágeno-Prolina Dioxigenasa/antagonistas & inhibidores , Quinolonas/farmacología , Técnicas Químicas Combinatorias , Dipéptidos/síntesis química , Dipéptidos/química , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Isoenzimas/química , Isoenzimas/metabolismo , Estructura Molecular , Procolágeno-Prolina Dioxigenasa/química , Procolágeno-Prolina Dioxigenasa/metabolismo , Quinolonas/síntesis química , Quinolonas/química , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
The bradykinin B1 receptor has been shown to mediate pain response and is rapidly induced upon injury. Blocking this receptor may provide a promising treatment for inflammation and pain. We previously reported tetralin benzyl amines as potent B1 antagonists. Here we describe the synthesis and SAR of B1 receptor antagonists with homobenzylic amines. The SAR of different linkers led to the discovery of tetralin allylic amines as potent and selective B1 receptor antagonists (hB1 IC(50)=1.3 nM for compound 16). Some of these compounds showed modest oral bioavailability in rats.
Asunto(s)
Bencilaminas/química , Antagonistas del Receptor de Bradiquinina B1 , Sulfonamidas/química , Tetrahidronaftalenos/química , Administración Oral , Animales , Dolor/tratamiento farmacológico , Ratas , Receptor de Bradiquinina B1/metabolismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/uso terapéuticoRESUMEN
Thiazolones with an exo-norbornylamine at the 2-position and an isopropyl group on the 5-position are potent 11beta-HSD1 inhibitors. However, the C-5 center was prone to epimerization in vitro and in vivo, forming a less potent diastereomer. A methyl group was added to the C-5 position to eliminate epimerization, leading to the discovery of (S)-2-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-ylamino)-5-isopropyl-5-methylthiazol-4(5H)-one (AMG 221). This compound decreased fed blood glucose and insulin levels and reduced body weight in diet-induced obesity mice.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Descubrimiento de Drogas/métodos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacología , Tiazoles/administración & dosificación , Tiazoles/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Administración Oral , Animales , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Masculino , Ratones , Modelos Moleculares , Conformación Proteica , Ratas , Tiazoles/química , Tiazoles/farmacocinéticaRESUMEN
Discovery and optimization of a piperidyl benzamide series of 11beta-HSD1 inhibitors is described. This series was derived from a cyclohexyl benzamide lead structures to address PXR selectivity, high non-specific protein binding, poor solubility, limited in vivo exposure, and in vitro cytotoxicity issues observed with the cyclohexyl benzamide structures. These efforts led to the discovery of piperidyl benzamide 15 which features improved properties over the cyclohexyl benzamide derivatives.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/síntesis química , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Insulina/metabolismo , Piperidinas/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Benzamidas/farmacología , Cristalografía por Rayos X/métodos , Diseño de Fármacos , Hepatocitos/efectos de los fármacos , Humanos , Concentración 50 Inhibidora , Microsomas/metabolismo , Modelos Químicos , Estructura Molecular , Solubilidad , Relación Estructura-ActividadRESUMEN
A series of compounds containing the 2-amino-1,3-thiazol-4(5H)-one core were found to be potent inhibitors of the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). One of our lead compounds from this series activated the human nuclear xenobiotic receptor, pregnane X receptor (PXR). To try and mitigate the PXR activity, we prepared analogues of our lead series that contained polar groups on the right-hand side of the thiazolone. Several analogues containing amides or alcohols appended to the C-5 position of the thiazolone showed a significant reduction in PXR activity. Through these structure-activity efforts, a compound containing a tert-alcohol group off the C-5 position, analogue (S)-33a, was found to have an 11beta-HSD1 Ki = 35 nM and negligible PXR activity. Compound (S)-33a was advanced into a pharmacodynamic model in cynomolgus monkeys, where it inhibited adipose 11beta-HSD1 activity after being orally administered.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Receptores de Esteroides/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Animales , Química Farmacéutica/métodos , Cristalografía por Rayos X/métodos , Citocromo P-450 CYP3A/química , Diseño de Fármacos , Humanos , Cinética , Macaca fascicularis , Masculino , Modelos Moleculares , Conformación Molecular , Receptor X de Pregnano , Distribución TisularRESUMEN
We report the development of aryl sulfones as Bradykinin B1 receptor antagonists. Variation of the linker region identified diol 23 as a potent B1 antagonist, while modifications of the aryl moiety led to compound 26, both of which were efficacious in rabbit biochemical challenge and pain models.
Asunto(s)
Antagonistas del Receptor de Bradiquinina B1 , Dolor/tratamiento farmacológico , Sulfonas/farmacología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/farmacología , Antagonistas del Receptor de Bradiquinina B2 , Enfermedad Crónica , Humanos , Conejos , Ratas , Ratas Sprague-Dawley , Sulfonas/administración & dosificaciónRESUMEN
Replacement of the core beta-amino acid in our previously reported piperidine acetic acid and beta-phenylalanine-based Bradykinin B1 antagonists by dihydroquinoxalinone acetic acid increases the in vitro potency and metabolic stability. The most potent compounds from this series have IC(50)s<0.2 nM in a human B1 receptor functional assay. A molecular modeling study of the binding modes of key compounds, based on a B1 homology model, explains the structure-activity relationship (SAR) for these analogs.
Asunto(s)
Acetamidas/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Química Farmacéutica/métodos , Quinoxalinas/síntesis química , Receptor de Bradiquinina B1/química , Acetamidas/química , Ácido Acético/química , Aminas , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Ligandos , Modelos Químicos , Conformación Molecular , Estructura Molecular , Unión Proteica , Quinoxalinas/farmacología , Relación Estructura-ActividadRESUMEN
We report the discovery of potent benzamide inhibitors of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1). The optimization and correlation of in vitro and in vivo metabolic stability will be described. Through modifications to our initial lead 2, we discovered pyridyl compound 13. This compound has a favorable pharmacokinetic profile across three species and showed a dose-dependent decrease in adipose 11beta-HSD1 activity in a monkey ex vivo pharmacodynamic model.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Benzamidas/administración & dosificación , Benzamidas/síntesis química , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Administración Oral , Animales , Benzamidas/química , Benzamidas/metabolismo , Línea Celular , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/metabolismo , Humanos , Macaca fascicularis , Modelos Animales , Modelos Moleculares , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
Inhibition of the PHD2 enzyme has been associated with increased red blood cell levels. From a screening hit, a series of novel hydroxyl-thiazoles were developed as potent PHD2 inhibitors.
Asunto(s)
Subunidad alfa del Factor 1 Inducible por Hipoxia/síntesis química , Tiazoles/química , Química Farmacéutica/métodos , Diabetes Mellitus/tratamiento farmacológico , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Eritrocitos/enzimología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/química , Concentración 50 Inhibidora , Modelos Químicos , Modelos Moleculares , Infarto del Miocardio/tratamiento farmacológico , Enfermedades Vasculares Periféricas/terapia , Accidente Cerebrovascular/tratamiento farmacológico , Relación Estructura-Actividad , Tiazoles/farmacologíaRESUMEN
A series of 2-anilinothiazolones were prepared as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). The most potent compounds contained a 2-chloro or 2-fluoro group on the aniline ring with an isopropyl substituent on the 5-position of the thiazolone ring (compounds 2 and 3, respectively). The binding mode was determined through the X-ray co-crystal structure of the enzyme with compound 3. This compound was also approximately 70-fold selective over 11beta-HSD2 and was orally bioavailable in rat pharmacokinetic studies. However, compound 3 was >580-fold less active in the 11beta-HSD1 cell assay when tested in the presence of 3% human serum albumin.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Tiazoles/química , Tiazoles/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Animales , Células CHO , Cloro/química , Cricetinae , Cricetulus , Cristalografía por Rayos X , Flúor/química , Humanos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tiazoles/clasificaciónRESUMEN
A simple, scalable, and efficient one-pot methodology for the synthesis of 4,4-disubstituted cyclohexane beta-keto esters from benzylic nitriles or esters and methyl acrylate promoted by potassium tert-butoxide is described. The process relies on a tandem double Michael addition-Dieckmann condensation reaction, which results in the formation of three discrete carbon-carbon bonds in a single pot, including a quaternary center. The method allows for the convenient and rapid synthesis of a variety of 4-aryl-4-cyano-2-carbomethoxycyclohexanone and 4-aryl-2,4-biscarbomethoxycyclohexanone building blocks for use in natural products synthesis and medicinal chemistry.
Asunto(s)
Ciclohexanonas/química , Ésteres/químicaRESUMEN
The bradykinin B1 receptor is induced following tissue injury and/or inflammation. Antagonists of this receptor have been studied as promising candidates for treatment of chronic pain. We have identified aryl sulfonamides containing a chiral chroman diamine moiety that are potent antagonists of the human B1 receptor. Our previously communicated lead, compound 2, served as a proof-of-concept molecule, but suffered from poor pharmacokinetic properties. With guidance from metabolic profiling, we performed structure-activity relationship studies and have identified potent analogs of 2. Variation of the sulfonamide moiety revealed a preference for 3- and 3,4-disubstituted aryl sulfonamides, while bulky secondary and tertiary amines were preferred at the benzylic amine position for potency at the B1 receptor. Modifying the beta-amino acid core of the molecule lead to the discovery of highly potent compounds with improved in vitro pharmacokinetic properties. The most potent analog at the human receptor, compound 38, was also active in a rabbit B1 receptor cellular assay. Furthermore, compound 38 displayed in vivo activity in two rabbit models, a pharmacodynamic model with a blood pressure readout and an efficacy model of inflammatory pain.
Asunto(s)
Amidas/síntesis química , Analgésicos/síntesis química , Benzopiranos/síntesis química , Antagonistas del Receptor de Bradiquinina B1 , Cromanos/síntesis química , Sulfonamidas/síntesis química , Amidas/farmacocinética , Amidas/farmacología , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Benzopiranos/farmacocinética , Benzopiranos/farmacología , Presión Sanguínea/efectos de los fármacos , Células CHO , Calcio/metabolismo , Cromanos/farmacocinética , Cromanos/farmacología , Cricetinae , Cricetulus , Humanos , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Masculino , Microsomas/metabolismo , Dolor/tratamiento farmacológico , Conejos , Ratas , Ratas Sprague-Dawley , Receptor de Bradiquinina B1/agonistas , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologíaRESUMEN
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is the enzyme that converts cortisone to cortisol. A growing body of evidence suggests that selective inhibition of 11beta-HSD1 could potentially treat metabolic syndrome as well as type 2 diabetes. Through modification of our initial lead 1, we have discovered trifluoromethyl thiazolone 17. This compound had a Ki of 22 nM, possessed low in vivo clearance, and showed a 91% inhibition of adipose 11beta-HSD1 enzymatic activity in a mouse ex vivo pharmacodynamic model.
Asunto(s)
Tiazoles/síntesis química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , Tejido Adiposo/enzimología , Administración Oral , Animales , Disponibilidad Biológica , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Tiazoles/farmacocinética , Tiazoles/farmacologíaRESUMEN
A thiazole derivative, 2-(2,6-dichlorobenzyl)-N-(4-isopropylphenyl) thiazole-4-carboxamide (1), was identified as a TRPV1 antagonist. We synthesized various thiazole analogs and evaluated them for their ability to block capsaicin- or acid-induced calcium influx in TRPV1-expressing CHO cells. The IC(50) values of the most potent antagonists were ca. 0.050microM in these assays.
Asunto(s)
Amidas/química , Amidas/farmacología , Canales Catiónicos TRPV/antagonistas & inhibidores , Tiazoles/química , Tiazoles/farmacología , Amidas/síntesis química , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Estructura Molecular , Ácido Oxámico/síntesis química , Ácido Oxámico/química , Ácido Oxámico/farmacología , Relación Estructura-Actividad , Tiazoles/síntesis químicaRESUMEN
An azo-dye lead was modified to a novel N-(1,3-thiazol-2-yl)pyridin-2-amine series of KDR kinase inhibitors through the use of rapid analog libraries. This new class has been found to be potent, selective, and of low molecular weight. Molecular modeling has postulated an interesting conformational preference and binding mode for these compounds in the active site of the enzyme.
Asunto(s)
Aminas/farmacología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Aminas/síntesis química , Sitios de Unión , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Unión Proteica , Conformación Proteica/efectos de los fármacos , Relación Estructura-Actividad , Termodinámica , Receptor 2 de Factores de Crecimiento Endotelial Vascular/químicaRESUMEN
We have discovered 3-(5-thien-3-ylpyridin-3-yl)-1H-indoles as potent inhibitors of KDR kinase activity. This communication details the evolution of this novel class from a potent screening lead of vastly different structure with an emphasis on structural modifications that retained activity and provided improvements in key physical properties. The synthesis and in-depth evaluation of these inhibitors are described.
Asunto(s)
Inhibidores de la Angiogénesis/síntesis química , Indoles/síntesis química , Indoles/farmacocinética , Receptor 2 de Factores de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Administración Oral , Inhibidores de la Angiogénesis/farmacocinética , Inhibidores de la Angiogénesis/farmacología , Animales , Disponibilidad Biológica , Línea Celular , Semivida , Indoles/farmacología , Concentración 50 Inhibidora , Ratas , Relación Estructura-ActividadRESUMEN
1,5-Diarylbenzimidazoles have been identified as potent inhibitors of KDR kinase activity. The series was developed with a goal of finding compounds with optimal drug-like properties. This communication describes structural modifications in the series that enhance solubility, lower protein binding, and provide compounds with excellent potency and pharmacokinetic profiles.