RESUMEN
We report on the development of a series of pyrimidine carboxylic acids that are potent and selective inhibitors of kynurenine monooxygenase and competitive for kynurenine. We describe the SAR for this novel series and report on their inhibition of KMO activity in biochemical and cellular assays and their selectivity against other kynurenine pathway enzymes. We describe the optimization process that led to the identification of a program lead compound with a suitable ADME/PK profile for therapeutic development. We demonstrate that systemic inhibition of KMO in vivo with this lead compound provides pharmacodynamic evidence for modulation of kynurenine pathway metabolites both in the periphery and in the central nervous system.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Enfermedad de Huntington/tratamiento farmacológico , Quinurenina 3-Monooxigenasa/antagonistas & inhibidores , Pirimidinas/farmacología , Animales , Células CHO , Proliferación Celular/efectos de los fármacos , Cricetulus , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Enfermedad de Huntington/metabolismo , Quinurenina/metabolismo , Quinurenina 3-Monooxigenasa/metabolismo , Ratones , Modelos Moleculares , Estructura Molecular , Pirimidinas/síntesis química , Pirimidinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Accumulation of amyloid ß (Aß) in brain is a pathological hallmark of Alzheimer's disease (AD). Aß is generated after sequential cleavage of its parental molecule, amyloid precursor protein (APP), by ß- and γ-secretases. Inhibition of γ-secretase activity is an effective approach for the reduction of Aß levels. Since γ-secretase targets many different substrates, selective inhibition of its cleavage of APP is believed to be critical in order to avoid undesirable side effects. γ-Secretase modulator (GSM) shifts the cleavage site on APP and production of amyloidogenic to non-amyloidogenic Aß fragments. Since GSMs only modulate and do not block cleavage of γ-secretase substrates, they are believed less likely to produce untoward adverse reactions. Here, we report in vivo Aß-lowering profiles of a pyridazine and a pyridine-derived GSM: GSM-C (Wan et al., 2011a) and GSM-D (Wan et al., 2011b). Both compounds reduced Aß40 and Aß42 productions, increased shorter Aß fragments, and had little effect on Notch signaling (â¼100-fold selective). They had excellent oral bioavailability (97.8% for GSM-C, â¼100% for GSM-D) and good brain permeability (free brain to free blood AUC ratio of 0.41 and 1.10 for GSM-C and GSM-D, respectively). Oral administration of these compounds in both acute and sub-chronic conditions reduced Aß levels in plasma and brain in rats in a dose- and time-dependent manner. Therefore, GSM-C and GSM-D represent two GSMs that are orally bioavailable and brain-permeable. They could serve as excellent tools in the investigation of the role of Aß peptides in AD pathogenesis.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Piridazinas/farmacología , Piridazinas/farmacocinética , Piridinas/farmacología , Piridinas/farmacocinética , Administración Oral , Péptidos beta-Amiloides/sangre , Animales , Disponibilidad Biológica , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Masculino , Neuronas/enzimología , Neuronas/metabolismo , Cultivo Primario de Células , Piridazinas/administración & dosificación , Piridinas/administración & dosificación , Ratas , Receptores Notch/metabolismo , Timocitos/efectos de los fármacosRESUMEN
SAR of a novel series of pyridine-derived γ-secretase modulators is described. Compound 5 was found to be a potent modulator in vitro, which on further profiling, was found to decrease Aß42 and Aß40, and maintain (or increase) the levels of total Aß. Furthermore, representative compounds 1 and 5 demonstrated in vivo efficacy to lower Aß42 in the brain without altering Notch processing in the peripheral.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Piridinas/farmacología , Animales , Disponibilidad Biológica , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Ratas , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of 3-amino-6-aryl-pyridazines have been identified as CB(2) agonists with high efficacy and selectivity against the CB(1) receptor. Details of the investigation of structure-activity relationships (SAR) are disclosed, which led to the identification of pyridazine analogue 35, a compound with high potency in an in vivo model of inflammatory pain.
Asunto(s)
Antiinflamatorios/síntesis química , Isoquinolinas/síntesis química , Piridazinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacocinética , Isoquinolinas/química , Isoquinolinas/farmacocinética , Dolor/tratamiento farmacológico , Piridazinas/química , Piridazinas/farmacocinética , Ratas , Receptor Cannabinoide CB2/metabolismo , Relación Estructura-ActividadRESUMEN
A chiral pseudo-C(3)-symmetric titanium triflate that employs the point chirality of a single stereogenic centre to control the propeller chirality of its aryl rings has been used to catalyse an asymmetric sulfoxidation reaction.
Asunto(s)
Mesilatos/química , Sulfóxidos/química , Titanio/química , Catálisis , Conformación Molecular , EstereoisomerismoRESUMEN
We report the synthesis and SAR of a series of novel azaindole CB(2) agonists. 6-Azaindole 18 showed activity in an acute pain model but was inactive in a chronic model. 18 is a Pgp substrate with low brain penetration. The template was redesigned, and the resulting 5-azaindole 36 was a potent CB(2) agonist with high CNS penetration. This compound was efficacious in the acute model and the chronic joint pain model.
Asunto(s)
Aminopiridinas/uso terapéutico , Encéfalo/metabolismo , Morfolinas/uso terapéutico , Dolor/tratamiento farmacológico , Receptor Cannabinoide CB2/agonistas , Aminopiridinas/farmacocinética , Animales , Compuestos Aza , Células CHO , Línea Celular , Enfermedad Crónica , Cricetinae , Cricetulus , Descubrimiento de Drogas , Humanos , Indoles , Morfolinas/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
We describe herein the medicinal chemistry approach which led to the discovery of a novel pyridine-3-carboxamide series of CB(2) receptor agonists. The SAR of this new template was evaluated and culminated in the identification of analogue 14a which demonstrated efficacy in an in vivo model of inflammatory pain.
Asunto(s)
Analgésicos/síntesis química , Piridinas/síntesis química , Piridinas/uso terapéutico , Receptor Cannabinoide CB2/agonistas , Amidas/síntesis química , Amidas/farmacología , Amidas/uso terapéutico , Analgesia/métodos , Animales , Modelos Animales de Enfermedad , Descubrimiento de Drogas/métodos , Inflamación , Dolor/tratamiento farmacológico , Piridinas/farmacología , Relación Estructura-ActividadRESUMEN
Selective CB2 receptor agonists are promising potential therapeutic agents for the treatment of inflammatory and neuropathic pain. A focused screen identified a pyrimidine ester as a partial agonist at the CB2 receptor with micromolar potency. Subsequent lead optimization identified 35, GW842166X, as the optimal compound in the series. 35 has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain and was selected as a clinical candidate for this indication.
Asunto(s)
Analgésicos/síntesis química , Dolor/tratamiento farmacológico , Piranos/síntesis química , Pirimidinas/síntesis química , Receptor Cannabinoide CB2/agonistas , Analgésicos/farmacocinética , Analgésicos/farmacología , Animales , Disponibilidad Biológica , Semivida , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Dolor/metabolismo , Piranos/farmacocinética , Piranos/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
An enantiopure amine tris(phenolate) ligand containing a single stereogenic center has been used to control the propeller-like chirality of a derived pseudo-C3-symmetric titanium isopropoxide complex with excellent levels of diastereocontrol. [structure: see text].
Asunto(s)
Compuestos Organometálicos/química , Titanio/química , Cristalografía por Rayos X , Ligandos , Espectroscopía de Resonancia Magnética/métodos , Modelos Moleculares , Estructura Molecular , Sensibilidad y Especificidad , EstereoisomerismoRESUMEN
The title binaphthyls 19 and 26, which are the positional isomers of 2-methoxy-2'-(diphenylphosphino)-1,1'-binaphthyl (MOP, 19) and 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN, 26), have been synthesized by Suzuki coupling as the key step (10 + 15-->18), followed by functional group transformations, involving C-P and C-N bond formation (18-->19 and 18-->23). Racemic intermediate 22 was resolved by co-crystallization with N-benzylcinchonidinium chloride and the absolute configuration determined by X-ray crystallography. These novel binaphthyls are configurationally stable and, as such, potentially usable as chiral ligands in asymmetric reactions. Michael addition of the glycine-derived enolate 40 to methyl acrylate, carried out in the presence of (R)-(-)-27 as the chiral phase-transfer catalyst, afforded L-glutamic acid (S)-(+)-43 of 92% ee (after hydrolysis of the primary product).
RESUMEN
The stable, readily available molybdenum(II) complexes [Mo(CO)(4)Br(2)](2) (B) and Mo(CO)(3)(MeCN)(2)(SnCl(3))Cl (C) have been found to catalyze C-C bond-forming allylic substitution with electron-rich aromatics (e.g., 15 + PhOMe --> 62) and heteroaromatics (e.g., 15 + 36 --> 88) as nucleophiles under mild conditions (room temperature, 30 min-3 h). Remarkable is the para-selectivity for anisole, whereas phenol tends to favor ortho-substitution in certain instances. Mechanistic and stereochemical experiments are indicative of Lewis-acid catalysis rather than a metal template-controlled process.