RESUMEN
The design, synthesis and structure-activity relationships of a novel series of 3,4-disubstituted pyrrolidine acid analogs as PPAR ligands is outlined. In both the 1,3- and 1,4-oxybenzyl pyrrolidine acid series, the preferred stereochemistry was shown to be the cis-3R,4S isomer, as exemplified by the potent dual PPARα/γ agonists 3k and 4i. The N-4-trifluoromethyl-pyrimidinyl pyrrolidine acid analog 4i was efficacious in lowering fasting glucose and triglyceride levels in diabetic db/db mice.
Asunto(s)
Hipoglucemiantes/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Pirrolidinas/química , Animales , Glucemia/análisis , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diseño de Fármacos , Femenino , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Ligandos , Ratones , Ratones Obesos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Pirrolidinas/síntesis química , Pirrolidinas/uso terapéutico , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
In this Letter, we describe the synthesis of several nonamidine analogs of biaryl acid factor VIIa inhibitor 1 containing weakly basic or nonbasic P1 groups. 2-Aminoisoquinoline was found to be an excellent surrogate for the benzamidine group (compound 2) wherein potent inhibition of factor VIIa is maintained relative to most other related serine proteases. In an unanticipated result, the m-benzamide P1 (compounds 21a and 21b) proved to be a viable benzamidine replacement, albeit with a 20-40 fold loss in potency against factor VIIa.
Asunto(s)
Ácidos Carboxílicos/química , Descubrimiento de Drogas , Factor VIIa/antagonistas & inhibidores , Inhibidores de Serina Proteinasa/química , Inhibidores de Serina Proteinasa/farmacología , Benzamidinas , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Factor VIIa/metabolismo , Humanos , Modelos Moleculares , Estructura Molecular , Inhibidores de Serina Proteinasa/síntesis química , Relación Estructura-ActividadRESUMEN
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
Asunto(s)
Neoplasias de la Mama , Ciclo Celular , Quinasas Ciclina-Dependientes , Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas , Animales , Femenino , Humanos , Ratones , Apoptosis , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Proliferación Celular , Quinasa Activadora de Quinasas Ciclina-Dependientes , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Ratones Endogámicos BALB C , Ratones Desnudos , Inhibidores de Proteínas Quinasas/farmacología , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Design, synthesis, and SAR of 7-oxopyrrolopyridine-derived DPP4 inhibitors are described. The preferred stereochemistry of these atropisomeric biaryl analogs has been identified as Sa. Compound (+)-3t, with a K(i) against DPP4, DPP8, and DPP9 of 0.37 nM, 2.2, and 5.7 µM, respectively, showed a significant improvement in insulin response after single doses of 3 and 10 µmol/kg in ob/ob mice.
Asunto(s)
Citocromo P-450 CYP3A/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Canales de Potasio Éter-A-Go-Go/metabolismo , Piridinas/química , Piridinas/farmacología , Animales , Dominio Catalítico , Diabetes Mellitus/tratamiento farmacológico , Inhibidores de la Dipeptidil-Peptidasa IV/farmacocinética , Humanos , Insulina/sangre , Insulina/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Piridinas/farmacocinética , Pirroles/química , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , EstereoisomerismoRESUMEN
Several pyrazolo-, triazolo-, and imidazolopyrimidines were synthesized and evaluated as inhibitors of DPP4. Of these three classes of compounds, the imidazolopyrimidines displayed the greatest potency and demonstrated excellent selectivity over the other dipeptidyl peptidases. SAR evaluation for these scaffolds was described as they may represent potential treatments for type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/síntesis química , Inhibidores de Proteasas/síntesis química , Pirimidinas/química , Dipeptidil Peptidasa 4/metabolismo , Humanos , Hipoglucemiantes/química , Hipoglucemiantes/uso terapéutico , Inhibidores de Proteasas/química , Inhibidores de Proteasas/uso terapéutico , Pirimidinas/síntesis química , Pirimidinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
The design, synthesis and structure-activity relationships of a novel series of N-phenyl-substituted pyrrole, 1,2-pyrazole and 1,2,3-triazole acid analogs as PPAR ligands are outlined. The triazole acid analogs 3f and 4f were identified as potent dual PPARalpha/gamma agonists both in binding and functional assays in vitro. The 3-oxybenzyl triazole acetic acid analog 3f showed excellent glucose and triglyceride lowering in diabetic db/db mice.
Asunto(s)
Azoles/síntesis química , Diseño de Fármacos , PPAR alfa/agonistas , PPAR gamma/agonistas , Animales , Azoles/farmacología , Línea Celular/enzimología , Cristalografía por Rayos X , Femenino , Humanos , Concentración de Iones de Hidrógeno , Ratones , Ratones Transgénicos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Relación Estructura-ActividadRESUMEN
3-hydroxy-3-methylglutaryl coenzyme-A reductase (HMGR) inhibitors, more commonly known as statins, represent the gold standard in treating hypercholesterolemia. Although statins are regarded as generally safe, they are known to cause myopathy and, in rare cases, rhabdomyolysis. Statin-dependent effects on plasma lipids are mediated through the inhibition of HMGR in the hepatocyte, whereas evidence suggests that myotoxicity is due to inhibition of HMGR within the myocyte. Thus, an inhibitor with increased selectivity for hepatocytes could potentially result in an improved therapeutic window. Implementation of a strategy that focused on in vitro potency, compound polarity, cell selectivity, and oral absorption, followed by extensive efficacy and safety modeling in guinea pig and rat, resulted in the identification of compound 1b (BMS-644950). Using this discovery pathway, we compared 1b to other marketed statins to demonstrate its outstanding efficacy and safety profile. With the potential to generate an excellent therapeutic window, 1b was advanced into clinical development.
Asunto(s)
Hidroximetilglutaril-CoA Reductasas/metabolismo , Inhibidores de Hidroximetilglutaril-CoA Reductasas/síntesis química , Pirimidinas/síntesis química , Triazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Colesterol/biosíntesis , Colesterol/sangre , Cristalografía por Rayos X , Perros , Femenino , Cobayas , Haplorrinos , Humanos , Hidroximetilglutaril-CoA Reductasas/química , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/toxicidad , Técnicas In Vitro , Hígado/efectos de los fármacos , Hígado/metabolismo , Modelos Moleculares , Células Musculares/citología , Células Musculares/efectos de los fármacos , Células Musculares/metabolismo , Pirimidinas/farmacología , Pirimidinas/toxicidad , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Triazoles/farmacología , Triazoles/toxicidadRESUMEN
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
Several series of substituted dehydropiperidine and piperidine-4-carboxylic acid analogs have been designed and synthesized as novel, potent dual PPARalpha/gamma agonists. The SAR of these series of analogs is discussed. A rare double bond migration occurred during the basic hydrolysis of the alpha,beta-unsaturated dehydropiperidine esters 12, and the structures of the migration products were confirmed through a series of 2D NMR experiments.
Asunto(s)
Ácidos Carboxílicos , PPAR alfa/agonistas , PPAR gamma/agonistas , Piperidinas , Unión Competitiva/efectos de los fármacos , Ácidos Carboxílicos/síntesis química , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Piperidinas/síntesis química , Piperidinas/química , Piperidinas/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel class of azetidinone acid-derived dual PPARalpha/gamma agonists has been synthesized for the treatment of diabetes and dyslipidemia. The preferred stereochemistry in this series for binding and functional agonist activity against both PPARalpha and PPARgamma receptors was shown to be 3S,4S. Synthesis, in vitro and in vivo activities of compounds in this series are described. A high-yielding method for N-arylation of azetidinone esters is also described.
Asunto(s)
Azetidinas/química , Azetidinas/farmacología , PPAR alfa/agonistas , PPAR gamma/agonistas , Administración Oral , Animales , Azetidinas/síntesis química , Disponibilidad Biológica , Cobre/farmacología , Cristalografía por Rayos X , Inhibidores Enzimáticos del Citocromo P-450 , Diabetes Mellitus Experimental/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/metabolismo , Glucosa/metabolismo , Ratones , Ratones Mutantes , Estructura Molecular , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Conformación Proteica , Estereoisomerismo , Relación Estructura-Actividad , Triglicéridos/sangreRESUMEN
Several series of pyridine amides were identified as selective and potent 11beta-HSD1 inhibitors. The most potent inhibitors feature 2,6- or 3,5-disubstitution on the pyridine core. Various linkers (CH(2)SO(2), CH(2)S, CH(2)O, S, O, N, bond) between the distal aryl and central pyridyl groups are tolerated, and lipophilic amide groups are generally favored. On the distal aryl group, a number of substitutions are well tolerated. A crystal structure was obtained for a complex between 11beta-HSD1 and the most potent inhibitor in this series.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Amidas/síntesis química , Amidas/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Amidas/química , Técnicas Químicas Combinatorias , Cristalografía por Rayos X , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Conformación Molecular , Estructura Molecular , Piridinas/química , Relación Estructura-ActividadRESUMEN
A novel series of imidazolin-2-ones were designed and synthesized as highly potent, orally active and muscle selective androgen receptor modulators (SARMs), with most of the compounds exhibiting low nM in vitro potency in androgen receptor (AR) binding and functional assays. Once daily oral treatment with the lead compound 11a (AR Ki = 0.9 nM, EC50 = 1.8 nM) for 14 days induced muscle growth with an ED50 of 0.09 mg/kg, providing approximately 50-fold selectivity over prostate growth in an orchidectomized rat model. Pharmacokinetic studies in rats demonstrated that the lead compound 11a had oral bioavailability of 65% and a plasma half-life of 5.5 h. On the basis of their preclinical profiles, the SARMs in this series are expected to provide beneficial anabolic effects on muscle with minimal androgenic effects on prostate tissue.
Asunto(s)
Anabolizantes/síntesis química , Imidazoles/síntesis química , Músculo Esquelético/efectos de los fármacos , Pirroles/síntesis química , Receptores Androgénicos/metabolismo , Administración Oral , Anabolizantes/farmacocinética , Anabolizantes/farmacología , Animales , Disponibilidad Biológica , Cristalografía por Rayos X , Semivida , Imidazoles/farmacocinética , Imidazoles/farmacología , Masculino , Modelos Moleculares , Músculo Esquelético/anatomía & histología , Orquiectomía , Próstata/anatomía & histología , Próstata/efectos de los fármacos , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
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
Alkyl quinolone molecules 2-heptyl-4-quinolone (HHQ) and 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) are important quorum sensing signals, which play a mediatory role in the pathogenesis of acute and chronic Pseudomonas aeruginosa infection. A targeted approach inhibiting the bacterial 'multiple virulence factor regulon' (MvfR) protein complex, offers the possibility to block the synthesis of MvfR-dependant signal molecules. Here, a high throughput bioanalytical method was developed using LC-MS/MS detection for the selective determination of HHQ and PQS in mouse tissue homogenate, over a sensitive range of 1-5000 and 10-5000pg/mL, respectively. Chromatographic peak distortion of the iron chelator PQS was overcome with the applied use of a bidentate chelator mobile phase additive 2-Picolinic acid at 0.2mM concentration, giving an improved separation and response for the analyte, whilst maintaining overall MS system robustness. Following thigh infection with P. aeruginosa strain 2-PA14 in mice, the concentration and time course of HHQ and PQS (4-hydroxy-2-alkyl-quinolone (HAQ) biomarkers) residing in the biophase were evaluated, and exhibited a low level combined with a substantial inter-individual variability. Quantifiable levels could be obtained from approximately 15h post infection, to the study termination at 21-22h. A dose dependant reduction in HAQ tissue concentrations at selected time points were obtained following MvfR inhibitor administration versus drug vehicle (p<0.01, Kruskal-Wallis-one way ANOVA) and meta -analyses of several studies enabled an inhibitory concentration (IC50) of 80nM free drug to be determined. However, due to the experimental limitations a defined time profile for in-vivo HAQ production could not be characterised. Microsomal stability measurements demonstrated a rapid metabolic clearance of both alkyl quinolone biomarkers in the bacterial host, with a hepatic extraction ratio greater than 0.96 (the measurable assay limit). High clearance underpinned the low concentrations present in the well-perfused thigh tissue. Along with method development and validation details, this paper considers the kinetics of in-vivo HAQ bio-synthesis during Pseudomonas infection; and risks of biomarker over-estimation from samples which contain an exogenous population of bacteria.
Asunto(s)
4-Quinolonas/análisis , Infecciones por Pseudomonas , Pseudomonas aeruginosa/química , Percepción de Quorum , Espectrometría de Masas en Tándem/métodos , 4-Quinolonas/metabolismo , Animales , Cromatografía Liquida/métodos , Humanos , Ratones , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Músculo Esquelético/microbiología , Infecciones por Pseudomonas/metabolismo , Pseudomonas aeruginosa/metabolismo , Percepción de Quorum/fisiologíaRESUMEN
Pseudomonas aeruginosa is an important nosocomial pathogen that is frequently recalcitrant to available antibiotics, underlining the urgent need for alternative therapeutic options against this pathogen. Targeting virulence functions is a promising alternative strategy as it is expected to generate less-selective resistance to treatment compared to antibiotics. Capitalizing on our nonligand-based benzamide-benzimidazole (BB) core structure compounds reported to efficiently block the activity of the P. aeruginosa multiple virulence factor regulator MvfR, here we report the first class of inhibitors shown to interfere with PqsBC enzyme activity, responsible for the synthesis of the MvfR activating ligands HHQ and PQS, and the first to target simultaneously MvfR and PqsBC activity. The use of these compounds reveals that inhibiting PqsBC is sufficient to block P. aeruginosa's acute virulence functions, as the synthesis of MvfR ligands is inhibited. Our results show that MvfR remains the best target of this QS pathway, as we show that antagonists of this target block both acute and persistence-related functions. The structural properties of the compounds reported in this study provide several insights that are instrumental for the design of improved MvfR regulon inhibitors against both acute and persistent P. aeruginosa infections. Moreover, the data presented offer the possibility of a polypharmacology approach of simultaneous silencing two targets in the same pathway. Such a combined antivirulence strategy holds promise in increasing therapeutic efficacy and providing alternatives in the event of a single target's resistance development.
Asunto(s)
Polifarmacología , Pseudomonas aeruginosa/genética , Regulón/efectos de los fármacos , Tolerancia a Medicamentos , Inhibidores Enzimáticos/farmacología , Terapia Molecular Dirigida/métodos , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/enzimología , Virulencia/efectos de los fármacos , Factores de VirulenciaRESUMEN
BMS-711939 (3) is a potent and selective peroxisome proliferator-activated receptor (PPAR) α agonist, with an EC50 of 4 nM for human PPARα and >1000-fold selectivity vs human PPARγ (EC50 = 4.5 µM) and PPARδ (EC50 > 100 µM) in PPAR-GAL4 transactivation assays. Compound 3 also demonstrated excellent in vivo efficacy and safety profiles in preclinical studies and thus was chosen for further preclinical evaluation. The synthesis, structure-activity relationship (SAR) studies, and in vivo pharmacology of 3 in preclinical animal models as well as its ADME profile are described.
RESUMEN
In a previous report we demonstrated that merging together key structural elements present in an AT(1) receptor antagonist (1, irbesartan) with key structural elements in a biphenylsulfonamide ET(A) receptor antagonist (2) followed by additional optimization provided compound 3 as a dual-action receptor antagonist (DARA), which potently blocked both AT(1) and ET(A) receptors. Described herein are our efforts directed toward improving both the pharmacokinetic profile as well as the AT(1) and ET(A) receptor potency of 3. Our efforts centered on modifying the 2'-side chain of 3 and examining the isoxazolylsulfonamide moiety in 3. This effort resulted in the discovery of 7 as a highly potent second-generation DARA. Compound 7 also showed substantially improved pharmacokinetic properties compared to 3. In rats, DARA 7 reduced blood pressure elevations caused by intravenous infusion of Ang II or big ET-1 to a greater extent and with longer duration than DARA 3 or AT(1) or ET(A) receptor antagonists alone. Compound 7 clearly demonstrated superiority over irbesartan (an AT(1) receptor antagonist) in the normal SHR model of hypertension in a dose-dependent manner, demonstrating the synergy of AT(1) and ET(A) receptor blockade in a single molecule.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antagonistas de los Receptores de la Endotelina A , Isoxazoles/química , Isoxazoles/farmacología , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Administración Oral , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacocinética , Animales , Antihipertensivos/química , Antihipertensivos/farmacología , Disponibilidad Biológica , Compuestos de Bifenilo/química , Compuestos de Bifenilo/farmacología , Perros , Humanos , Hipertensión/tratamiento farmacológico , Irbesartán , Isoxazoles/farmacocinética , Macaca fascicularis , Masculino , Ratas , Ratas Endogámicas SHR , Relación Estructura-Actividad , Sulfonamidas/farmacocinética , Tetrazoles/química , Tetrazoles/farmacologíaRESUMEN
Optimization of a 5-oxopyrrolopyridine series based upon structure-activity relationships (SARs) developed from our previous efforts on a number of related bicyclic series yielded compound 2s (BMS-767778) with an overall activity, selectivity, efficacy, PK, and developability profile suitable for progression into the clinic. SAR in the series and characterization of 2s are described.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Dipeptidil Peptidasa 4/metabolismo , Inhibidores de la Dipeptidil-Peptidasa IV/química , Inhibidores de la Dipeptidil-Peptidasa IV/farmacología , Diseño de Fármacos , Pirroles/química , Pirroles/farmacología , Acetamidas/síntesis química , Animales , Compuestos Bicíclicos Heterocíclicos con Puentes/síntesis química , Dominio Catalítico , Dipeptidil Peptidasa 4/química , Inhibidores de la Dipeptidil-Peptidasa IV/síntesis química , Prueba de Tolerancia a la Glucosa , Humanos , Masculino , Ratones , Modelos Moleculares , Pirroles/síntesis química , Especificidad por SustratoRESUMEN
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.
Asunto(s)
Inhibidores de la Dipeptidil-Peptidasa IV , Hipoglucemiantes/síntesis química , Imidazoles/síntesis química , Pirimidinas/síntesis química , Animales , Dominio Catalítico , Cristalografía por Rayos X , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Dipeptidil Peptidasa 4/química , Perros , Canal de Potasio ERG1 , Canales de Potasio Éter-A-Go-Go/antagonistas & inhibidores , Humanos , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Imidazoles/farmacocinética , Imidazoles/farmacología , Masculino , Ratones , Ratones Obesos , Modelos Moleculares , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Bloqueadores de los Canales de Sodio/farmacología , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) alpha agonist, with an EC(50) of 10 nM for human PPARalpha and approximately 410-fold selectivity vs human PPARgamma in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPARdelta. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPARalpha ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPARalpha in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.