RESUMEN
The directed activation of carbon-hydrogen bonds (C-H) is important in the development of synthetically useful reactions, owing to the proximity-induced reactivity and selectivity that is enabled by coordinating functional groups. Palladium-catalysed non-directed C-H activation could potentially enable further useful reactions, because it can reach more distant sites and be applied to substrates that do not contain appropriate directing groups; however, its development has faced substantial challenges associated with the lack of sufficiently active palladium catalysts. Currently used palladium catalysts are reactive only with electron-rich arenes, unless an excess of arene is used, which limits synthetic applications. Here we report a 2-pyridone ligand that binds to palladium and accelerates non-directed C-H functionalization with arene as the limiting reagent. This protocol is compatible with a broad range of aromatic substrates and we demonstrate direct functionalization of advanced synthetic intermediates, drug molecules and natural products that cannot be used in excessive quantities. We also developed C-H olefination and carboxylation protocols, demonstrating the applicability of our methodology to other transformations. The site selectivity in these transformations is governed by a combination of steric and electronic effects, with the pyridone ligand enhancing the influence of sterics on the selectivity, thus providing complementary selectivity to directed C-H functionalization.
Asunto(s)
Carbono/química , Hidrocarburos Aromáticos/química , Hidrógeno/química , Piridonas/química , Alquenos/química , Productos Biológicos/química , Catálisis , Ligandos , Paladio/química , Preparaciones Farmacéuticas/químicaRESUMEN
A useful protocol for achieving decarboxylative cross-coupling (DCC) of redox-active esters (RAE, isolated or generated in situ) and halo(hetero)arenes is reported. This pragmatically focused study employs a unique Ag-Ni electrocatalytic platform to overcome numerous limitations that have plagued this strategically powerful transformation. In its optimized form, coupling partners can be combined in a surprisingly simple way: open to the air, using technical-grade solvents, an inexpensive ligand and Ni source, and substoichiometric AgNO3, proceeding at room temperature with a simple commercial potentiostat. Most importantly, all of the results are placed into context by benchmarking with state-of-the-art methods. Applications are presented that simplify synthesis and rapidly enable access to challenging chemical space. Finally, adaptation to multiple scale regimes, ranging from parallel milligram-based synthesis to decagram recirculating flow is presented.
Asunto(s)
Ésteres , Catálisis , Ligandos , Oxidación-Reducción , SolventesRESUMEN
In a Phase 2 clinical trial, BMS-986020, a lysophosphatidic acid receptor-1 (LPA1) antagonist, produced hepatobiliary toxicity (increased ALT, AST, and ALP; cholecystitis) and increases in plasma bile acids (BA). Nonclinical investigations conducted to identify a potential mechanism(s) for this toxicity examined BMS-986020 and two LPA1 antagonists structurally distinct from BMS-986020 (BMS-986234 and BMS-986278). BMS-986020 inhibited hepatic BA efflux transporters BSEP (IC50 1.8 µM), MRP3 (IC50 22 µM), and MRP4 (IC50 6.2 µM) and inhibited BA canalicular efflux in human hepatocytes (68% at 10 µM). BMS-986020 inhibited mitochondrial function (basal and maximal respiration, ATP production, and spare capacity) in human hepatocytes and cholangiocytes at ≥10 µM and inhibited phospholipid efflux in human hepatocytes (MDR3 IC50 7.5 µM). A quantitative systems toxicology analysis (DILIsym®), considering pharmacokinetics, BA homeostasis, mitochondrial function, oxidative phosphorylation, and reactive intermediates performed for BMS-986020 recapitulated clinical findings ascribing the effects to BA transporter and mitochondrial electron transport chain inhibition. BMS-986234 and BMS-986278 minimally inhibited hepatic BA transporters (IC50 ≥20 µM) and did not inhibit MDR3 activity (IC50 >100 µM), nor did BMS-986234 inhibit BA efflux (≤50 µM) or mitochondrial function (≤30 µM) (BMS-986278 not evaluated). Multiple mechanisms may be involved in the clinical toxicity observed with BMS-986020. The data indicate that this toxicity was unrelated to LPA1 antagonism since the mechanisms that likely influenced the adverse clinical outcome of BMS-986020 were not observed with equipotent LPA1 antagonists BMS-986234 and BMS-986278. This conclusion is consistent with the lack of hepatobiliary toxicity in nonclinical and clinical safety studies with BMS-986278.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedades del Sistema Digestivo/inducido químicamente , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Hígado/efectos de los fármacos , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Ácidos y Sales Biliares/metabolismo , Transporte Biológico/fisiología , Línea Celular , Línea Celular Tumoral , Transporte de Electrón/fisiología , Células HEK293 , Células Hep G2 , Hepatocitos/efectos de los fármacos , Humanos , Mitocondrias/efectos de los fármacosRESUMEN
We report here a catalytic method for the modular ring expansion of cyclic aliphatic alcohols. In this work, proton-coupled electron transfer activation of an allylic alcohol substrate affords an alkoxy radical intermediate that undergoes subsequent C-C bond cleavage to furnish an enone and a tethered alkyl radical. Recombination of this alkyl radical with the revealed olefin acceptor in turn produces a ring-expanded ketone product. The regioselectivity of this C-C bond-forming event can be reliably controlled via substituents on the olefin substrate, providing a means to convert a simple N-membered ring substrate to either n+1 or n+2 ring adducts in a selective fashion.
Asunto(s)
Alcoholes/química , Protones , Catálisis , Transporte de ElectrónRESUMEN
A quinoline-based ligand effectively promotes the palladium-catalyzed borylation of C(sp(3))-H bonds. Primary ß-C(sp(3))-H bonds in carboxylic acid derivatives as well as secondary C(sp(3))-H bonds in a variety of carbocyclic rings, including cyclopropanes, cyclobutanes, cyclopentanes, cyclohexanes, and cycloheptanes, can thus be borylated. This directed borylation method complements existing iridium(I)- and rhodium(I)-catalyzed C-H borylation reactions in terms of scope and operational conditions.
Asunto(s)
Compuestos de Boro/química , Paladio/química , Catálisis , Enlace de Hidrógeno , LigandosRESUMEN
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
Glucokinase (GK) catalyzes the initial step in glycolysis and is a key regulator of glucose homeostasis. Therefore, glucokinase activators (GKa) have potential benefit in treating type 2 diabetes. Administration of a Bristol-Myers Squibb GKa (BMS-820132) to healthy euglycemic Sprague-Dawley (SD) rats and beagle dogs in 1 mo toxicology studies resulted in marked and extended hypoglycemia with associated clinical signs of toxicity and degenerative histopathological changes in the stomach, sciatic nerve, myocardium, and skeletal muscles at exposures comparable to those expected at therapeutic clinical exposures. To investigate whether these adverse effects were secondary to exaggerated pharmacology (prolonged hypoglycemia), BMS-820132 was administered daily to male Zucker diabetic fatty (ZDF) rats for 1 mo. ZDF rats are markedly hyperglycemic and insulin resistant. BMS-820132 did not induce hypoglycemia, clinical signs of hypoglycemia, or any of the histopathologic adverse effects observed in the 1 mo toxicology studies at exposures that exceeded those observed in SD rats and dogs. This indicates that the toxicity observed in euglycemic animals was secondary to the exaggerated pharmacology of potent GK activation. This study indicates that ZDF rats, with conventional toxicity studies, are a useful disease model for testing antidiabetic agents and determining toxicities that are independent of prolonged hypoglycemia.
Asunto(s)
Diabetes Mellitus/genética , Activadores de Enzimas/toxicidad , Hipoglucemia/inducido químicamente , Hipoglucemiantes/toxicidad , Ratas Zucker/metabolismo , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Diabetes Mellitus/patología , Perros , Ingestión de Alimentos/efectos de los fármacos , Activadores de Enzimas/farmacocinética , Glucoquinasa/genética , Hipoglucemia/patología , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Insulina/sangre , Resistencia a la Insulina/genética , Masculino , Ratas , Especificidad de la Especie , ToxicocinéticaRESUMEN
The oxycyclohexyl acid BMS-986278 (33) is a potent lysophosphatidic acid receptor 1 (LPA1) antagonist, with a human LPA1 Kb of 6.9 nM. The structure-activity relationship (SAR) studies starting from the LPA1 antagonist clinical compound BMS-986020 (1), which culminated in the discovery of 33, are discussed. The detailed in vitro and in vivo preclinical pharmacology profiles of 33, as well as its pharmacokinetics/metabolism profile, are described. On the basis of its in vivo efficacy in rodent chronic lung fibrosis models and excellent overall ADME (absorption, distribution, metabolism, excretion) properties in multiple preclinical species, 33 was advanced into clinical trials, including an ongoing Phase 2 clinical trial in patients with lung fibrosis (NCT04308681).
Asunto(s)
Descubrimiento de Drogas , Fibrosis Pulmonar/tratamiento farmacológico , Receptores del Ácido Lisofosfatídico/antagonistas & inhibidores , Animales , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Estructura Molecular , Fibrosis Pulmonar/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores del Ácido Lisofosfatídico/metabolismo , Relación Estructura-ActividadRESUMEN
The synthesis and follow-up SAR studies of our development candidate 1 by incorporating 2-aryl-4-oxazolylmethoxy and 2-aryl-4-thiazolylmethoxy moieties into the oxybenzylglycine framework of the PPARalpha/gamma dual agonist muraglitazar is described. SAR studies indicate that different substituents on the aryloxazole/thiazole moieties as well as the choice of carbamate substituent on the glycine moiety can significantly modulate the selectivity of PPARalpha versus PPARgamma. Potent, highly selective PPARalpha activators 2a and 2l, as well as PPARalpha activators with significant PPARgamma activity, such as 2s, were identified. The in vivo pharmacology of these compounds in preclinical animal models as well as their ADME profiles are discussed.
Asunto(s)
Antiinflamatorios/síntesis química , Glicina/análogos & derivados , PPAR alfa/agonistas , PPAR gamma/agonistas , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Sitios de Unión , Cricetinae , Cristalografía por Rayos X , Glicina/síntesis química , Glicina/farmacocinética , Humanos , Masculino , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Ratas , Ratas Sprague-Dawley , 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
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
A tetrazole-based peptidomimetic 2 (BMS-317180) was discovered as a human growth hormone secretagogue (GHS). Compound 2 is a potent, novel, orally effective GHS that shows an excellent safety profile in preclinical studies. The compound was advanced into clinical development.
Asunto(s)
Carbamatos/síntesis química , Hormona del Crecimiento/metabolismo , Tetrazoles/síntesis química , Administración Oral , Animales , Disponibilidad Biológica , Carbamatos/farmacocinética , Carbamatos/farmacología , Perros , Ésteres , Hormona del Crecimiento/sangre , Hormona de Crecimiento Humana/metabolismo , Humanos , Macaca fascicularis , Ratas , Solubilidad , Relación Estructura-Actividad , Tetrazoles/farmacocinética , Tetrazoles/farmacología , AguaRESUMEN
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
Muraglitazar/BMS-298585 (2) has been identified as a non-thiazolidinedione PPAR alpha/gamma dual agonist that shows potent activity in vitro at human PPARalpha (EC(50) = 320 nM) and PPARgamma(EC(50) = 110 nM). Compound 2 shows excellent efficacy for lowering glucose, insulin, triglycerides, and free fatty acids in genetically obese, severely diabetic db/db mice and has a favorable ADME profile. Compound 2 is currently in clinical development for the treatment of type 2 diabetes and dyslipidemia.
Asunto(s)
Glicina/análogos & derivados , Glicina/síntesis química , Hipoglucemiantes/síntesis química , Hipolipemiantes/síntesis química , Oxazoles/síntesis química , PPAR alfa/agonistas , PPAR gamma/agonistas , Adipocitos/citología , Animales , Glucemia/efectos de los fármacos , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Ácidos Grasos/sangre , Glicina/química , Glicina/farmacología , Humanos , Hiperlipidemias/tratamiento farmacológico , Hipoglucemiantes/farmacocinética , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacocinética , Hipolipemiantes/farmacología , Insulina/sangre , Masculino , Ratones , Ratones Obesos , Oxazoles/química , Oxazoles/farmacología , Activación Transcripcional , Triglicéridos/sangreRESUMEN
Peroxisome proliferator-activated receptors (PPARs) alpha, gamma and delta (beta) are ligand-activated transcription factors of the nuclear hormone receptor superfamily which have been shown to play key roles in maintaining glucose and lipid homeostasis. The physiological effects of several marketed drugs for the treatment of dyslipidemia (fenofibrate and gemfibrozil) and diabetes (rosiglitazone and pioglitazone) have now been shown to be mediated through PPARalpha and PPARgamma respectively. Over the past few years our understanding of how PPAR ligands and receptors modulate gene expression has greatly increased; this knowledge is being used to design even more potent and efficacious PPAR ligands for the treatment of diabetes, dyslipidemia, atherosclerosis and obesity. This review is a brief survey of the PPAR field which highlights recent progress, with an emphasis on new ligands with novel PPAR profiles, particularly compounds which are co-agonists of PPAalpha, gamma and beta (delta).
Asunto(s)
Antimetabolitos/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Homeostasis/efectos de los fármacos , Enfermedades Metabólicas/tratamiento farmacológico , Receptores Activados del Proliferador del Peroxisoma/metabolismo , Factores de Transcripción/efectos de los fármacos , Animales , Enfermedades Cardiovasculares/metabolismo , Sistemas de Liberación de Medicamentos , Glucosa/metabolismo , Homeostasis/fisiología , Humanos , Ligandos , Metabolismo de los Lípidos , Enfermedades Metabólicas/metabolismo , Receptores Activados del Proliferador del Peroxisoma/agonistas , Receptores Activados del Proliferador del Peroxisoma/antagonistas & inhibidores , Factores de Transcripción/metabolismoRESUMEN
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.
Asunto(s)
Descubrimiento de Drogas , Glicina/análogos & derivados , Oxazoles/química , Oxazoles/farmacología , PPAR alfa/agonistas , Animales , Línea Celular , Cricetinae , Cristalografía por Rayos X , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Glicina/síntesis química , Glicina/química , Glicina/farmacología , Glicina/toxicidad , Humanos , Masculino , Ratones , Modelos Moleculares , Oxazoles/síntesis química , Oxazoles/toxicidad , PPAR alfa/química , PPAR alfa/genética , Estructura Terciaria de Proteína , Especificidad por Sustrato , Activación Transcripcional/efectos de los fármacosRESUMEN
Peroxisome proliferator-activated receptors (PPARs) and other members of the nuclear hormone receptor family are important drug targets for the treatment of metabolic diseases. PPARalpha and PPARgamma play crucial roles in lipid and glucose metabolism, respectively. Therefore, screening methods that help to rapidly identify activators of these receptors should be of considerable value. A homogeneous fluorescence polarization (FP) ligand binding assay capable of rapidly identifying ligands that bind to both PPARalpha and PPARgamma has been developed using purified PPARalpha or PPARgamma ligand binding domains and a fluorescein-labeled analog (FLA) of a potent dual PPARalpha/gamma activator. FLA activator showed good binding affinity toward both PPARalpha (K(i)=0.7microM) and PPARgamma (K(i)=0.4microM). The binding of FLA activator was rapid and reached a plateau within 10 min. The resulting FP signal was stable for at least 18h. The FP binding assay performed robustly in a 384-well format, and the average Z' value was 0.77. There was a good correlation between the binding potency (IC(50) values) and rank order of binding potency for a panel of standard PPAR ligands obtained in FP binding assay and scintillation proximity assay or gel filtration binding assays using (3)H-labeled PPARalpha (r(2)=0.99) and PPARgamma (r(2)=0.99) ligands. There was also a good correlation of IC(50) values obtained by FP binding assay and scintillation proximity assay for the clinically used PPAR activators. Thus, the FP binding assay with a single fluorescein-labeled PPARalpha/gamma dual activator offers a homogeneous nonradioactive, sensitive, robust, and less expensive high-throughput assay for detecting compounds that bind to both PPARgamma and PPARalpha. Using this FP binding assay, we have identified a large number of PPARalpha/gamma dual activators. A similar assay platform may be easily adapted to other members of the nuclear hormone receptor family.
Asunto(s)
Polarización de Fluorescencia/métodos , Ligandos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Cromatografía en Gel , Dimetilsulfóxido/química , Humanos , Cinética , Modelos Biológicos , Estructura Molecular , PPAR alfa/agonistas , PPAR alfa/genética , PPAR gamma/agonistas , PPAR gamma/genética , Unión Proteica , Reproducibilidad de los ResultadosRESUMEN
A novel class of Growth Hormone Secretagogues (GHS), based on a tetrazole template, has been discovered. In vitro SAR and in vivo potency within this new class of GHS are described. The tetrazole 9q exhibits good oral bioavailability in rats and dogs as well as efficacy following an oral 10 mg/kg dose in dogs. Solution and solid phase protocols for the synthesis of tetrazole based GHS have been developed.
Asunto(s)
Hormona del Crecimiento/metabolismo , Tetrazoles/química , Tetrazoles/farmacología , Animales , Perros , Relación Estructura-Actividad , Tetrazoles/síntesis químicaRESUMEN
A novel series of potent dual agonists of PPARalpha and PPARgamma, the alkoxybenzylglycines, was identified and explored using a solution-phase library approach. The synthesis and structure-activity relationships of this series of dual PPARalpha/gamma agonists are described.