RESUMO
A new series of indole amide acting as hCRTH2 receptor ligands had been explored and are described herein. Several amide derivatives displaying low nanomolar activity in hCRTH2 binding and whole blood assays were identified. They were found to behave as a full antagonists, exhibiting good selectivity over related prostaglandin receptors. Also, prototypical compounds in this novel series which displayed acceptable CYP profiles and were orally bioavailable in rats were identified.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptores de Dopamina D2/agonistas , Amidas/química , Animais , Indóis/química , Concentração Inibidora 50 , Ligantes , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , RatosRESUMO
A novel series of EP(4) ligands, based on a benzyl indoline scaffold, has been discovered. It was found that agonism and antagonism in this series can be easily modulated by minor modifications on the benzyl group. The pharmacokinetic, metabolic and pharmacological profiles of these compounds was explored. It was found that these compounds show good pharmacokinetics in rat and are efficacious in pre-clinical models of pain and inflammation.
Assuntos
Indóis/química , Receptores de Prostaglandina E Subtipo EP4/agonistas , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Indóis/farmacocinética , Indóis/uso terapêutico , Ligantes , Ratos , Receptores de Prostaglandina E Subtipo EP2/agonistas , Receptores de Prostaglandina E Subtipo EP2/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Relação Estrutura-AtividadeRESUMO
A new class of 7-azaindole analogs of MK-7246 as potent and selective CRTH2 antagonists is reported. The SAR leading to the identification of the optimal azaindole regioisomer as well as the pharmacokinetics and off-target activities of the most potent antagonists are disclosed.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Animais , Carbolinas/química , Humanos , Indóis/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
In this manuscript we wish to report the discovery of MK-7246 (4), a potent and selective CRTH2 (DP2) antagonist. SAR studies leading to MK-7246 along with two synthetic sequences enabling the preparation of this novel class of CRTH2 antagonist are reported. Finally, the pharmacokinetic and metabolic profile of MK-7246 is disclosed.
Assuntos
Carbolinas/química , Pneumopatias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Carbolinas/farmacocinética , Carbolinas/uso terapêutico , Humanos , Macaca mulatta , Microssomos Hepáticos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Relação Estrutura-AtividadeRESUMO
The strategy and SAR studies that led to the discovery of a novel potent and orally available 5-lipoxygenase (5-LO) inhibitor 3-(4-fluorophenyl)-6-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-1-benzothiophene-2-carboxamide ((S)-2l or MK-5286) were described.
Assuntos
Araquidonato 5-Lipoxigenase/química , Hidrocarbonetos Fluorados/química , Inibidores de Lipoxigenase/química , Tiofenos/química , Triazóis/química , Administração Oral , Animais , Araquidonato 5-Lipoxigenase/metabolismo , Cães , Avaliação Pré-Clínica de Medicamentos , Humanos , Hidrocarbonetos Fluorados/síntese química , Hidrocarbonetos Fluorados/farmacologia , Inibidores de Lipoxigenase/síntese química , Inibidores de Lipoxigenase/farmacocinética , Ratos , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/farmacologia , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
The discovery of a highly potent and selective EP(4) antagonist MF-766 is discussed. This N-benzyl indole derivative exhibits good pharmacokinetic profile and unprecedented in vivo potency in the rat AIA model.
Assuntos
Benzoatos/farmacologia , Indóis/farmacologia , Dor/tratamento farmacológico , Receptores de Prostaglandina E/antagonistas & inibidores , Animais , Artrite/tratamento farmacológico , Benzoatos/química , Benzoatos/uso terapêutico , Células Cultivadas , Cães , Descoberta de Drogas , Estabilidade de Medicamentos , Hepatócitos , Humanos , Indóis/química , Indóis/uso terapêutico , Inflamação/tratamento farmacológico , Farmacocinética , Ratos , Receptores de Prostaglandina E Subtipo EP4 , Relação Estrutura-AtividadeRESUMO
Chronic obstructive pulmonary disease (COPD) is characterized by the degradation of elastin, the major insoluble protein of lung tissues. The degradation of elastin gives rise to desmosine (DES) and isodesmosine (IDES), two major urinary products typified by a hydrophilic pyridinium-based cross-linker structure. A high sensitivity method based on nanoflow liquid chromatography tandem mass spectrometry with multiple reaction monitoring was developed for the analysis of urinary DES and IDES. The analytes were derivatized with propionic anhydride and deuterated DES (D(4)-DES) was used as an internal standard. This method enables the quantification of DES and IDES in as little as 50 microL of urine and provides a detection limit of 0.10 ng/mL (0.95 fmol on-column). We report the analysis of DES and IDES in a cohort of 40 urine specimens from four groups of individuals: (a) COPD rapid decliners (11.8 +/- 3.7 ng/mg creatine (crea)), (b) COPD slow decliners (16.0 +/- 3.1 ng/mg crea), (c) healthy smokers (13.2 +/- 1.9 ng/mg crea), and (d) healthy nonsmokers (14.9 +/- 2.9 ng/mg crea). Our analysis reveals a statistically significant decrease in the level of urinary DES and IDES in COPD rapid decliner patients compared to healthy nonsmoker controls and COPD slow decliner patients. This methodology may be useful for monitoring DES and IDES levels in well controlled animal models for COPD or for longitudinal studies in COPD patients.
Assuntos
Cromatografia Líquida/métodos , Desmosina/urina , Isodesmosina/urina , Limite de Detecção , Espectrometria de Massas/métodos , Espectrometria de Massas em Tandem/métodos , Elastina/análise , HumanosRESUMO
A new series of indole-based antagonists of the PGD(2) receptor subtype 1 (DP1 receptor) was identified and the progress of the structure-activity relationship study to the identification of potent and selective antagonists is presented. Selective DP1 antagonists with high potency and selectivity were prepared. Of particular interest is the DP1 antagonist 26 with a K(i) value of 1 nM for the DP1 receptor and an IC(50) value of 4.6 nM in a DP1 functional assay for the inhibition of the PGD(2) induced cAMP production in platelet rich plasma (PRP).
Assuntos
Hidrogênio/química , Indóis/síntese química , Indóis/farmacologia , Piridinas/química , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Humanos , Indóis/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The discovery of the potent and selective prostaglandin D2 (PGD2) receptor (DP) antagonist [(3R)-4-(4-chlorobenzyl)-7-fluoro-5-(methylsulfonyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]-acetic acid (13) is presented. Initial lead antagonists 6 and 7 were found to be potent and selective DP antagonists (DP Ki = 2.0 nM for each); however, they both suffered from poor pharmacokinetic profiles, short half-lives and high clearance rates in rats. Rat bile duct cannulation studies revealed that high concentrations of parent drug were present in the biliary fluid (Cmax = 1100 microM for 6 and 3900 microM for 7). This pharmacokinetic liability was circumvented by replacing the 7-methylsulfone substituent present in 6 and 7 with a fluorine atom resulting in antagonists with diminished propensity for biliary excretion and with superior pharmacokinetic profiles. Further optimization led to the discovery of the potent and selective DP antagonist 13.
Assuntos
Indóis/síntese química , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Obstrução das Vias Respiratórias/tratamento farmacológico , Animais , Bile/metabolismo , Ligação Competitiva , Cães , Hepatócitos/metabolismo , Humanos , Técnicas In Vitro , Indóis/farmacocinética , Indóis/farmacologia , Macaca fascicularis , Masculino , Camundongos , Microssomos/metabolismo , Descongestionantes Nasais/síntese química , Descongestionantes Nasais/farmacocinética , Descongestionantes Nasais/farmacologia , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ovinos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Julia olefination between alpha-alkoxy sulfones 2a-c and a wide variety of ketones or aldehydes afforded substituted vinyl ethers in 46-90% yields. Sulfones 2a-c were readily prepared in two steps from commercially available reagents in 68-80% yields. Optimization revealed that the nature of the base, the solvent, and the temperature were crucial to obtaining the desired vinyl ethers. [reaction: see text]
RESUMO
It has been observed that 2-(E)-benzylidene-1-indanone (1) undergoes dimerization under basic conditions. The reaction is highly stereoselective and provides almost exclusively dimer 2b using NaHCO(3)/DMF, guanidine carbonate/DMF, or Cs(2)CO(3)/CH(3)CN. The structure and the relative stereochemistry of compound 2b were initially established on the basis of COSY, HMQC, HMBC, and NOESY NMR correlation techniques. The structure and the stereochemistry were then confirmed by X-ray crystallographic analysis. Two other stereoisomers were obtained, in minor proportions, by varying the experimental conditions. A fourth isomer was also produced using 2-(Z)-benzylidene-1-indanone as the starting material.
RESUMO
Nitrile-based inhibitors of cathepsin K have been known for some time and mechanism-of-action studies have demonstrated that cysteinyl proteases interact with nitriles in a reversible fashion. Three main classes of nitrile-containing inhibitors have been published in the cathepsin K field: (i) cyanamides, (ii) aromatic nitriles, and (iii) aminoacetonitriles. A computational approach was used to calculate the theoretical reactivities of diverse nitriles and this was found to correlate with their extent of reactivity with free cysteine. Moreover, there is a tentative link between high reactivity with cysteine and the potential to lead to irreversible covalent binding to proteins.
Assuntos
Inibidores de Cisteína Proteinase/síntese química , Nitrilas/química , Catepsina K , Catepsinas/antagonistas & inibidores , Biologia Computacional , Cisteína/química , Inibidores de Cisteína Proteinase/farmacologia , Eletroquímica , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , NADP/química , OxirreduçãoRESUMO
Some DP1 receptor antagonists from an indole-containing series were shown to cause in vitro covalent binding to protein in rat and human liver microsomes. Glutathione trapping experiments along with in vitro labeling assays confirmed that the presence of a strong electron withdrawing group was necessary to abrogate in vitro covalent binding, leading to the discovery of MK-0524. Hepatocyte incubations and in vivo studies showed that acyl-glucuronide formation did not translate into covalent binding.
Assuntos
Glutationa/metabolismo , Indóis/agonistas , Indóis/metabolismo , Microssomos Hepáticos/metabolismo , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Animais , Elétrons , Glucuronídeos/biossíntese , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Humanos , Indóis/química , Proteínas/metabolismo , RatosRESUMO
Metabolites of the potent DP antagonist, MK-0524, were generated using in vitro systems including hepatic microsomes and hepatocytes. Four metabolites (two hydroxylated diastereomers, a ketone and an acyl glucuronide) were characterized by LC-MS/MS and 1H NMR. Larger quantities of these metabolites were prepared by either organic synthesis or biosynthetically to be used as standards in other studies. The propensity for covalent binding was assessed and was found to be acceptable (<50 pmol-equiv/mg protein).
Assuntos
Indóis/síntese química , Indóis/farmacologia , Prostaglandina D2/antagonistas & inibidores , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Cães , Humanos , Macaca mulatta , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Microssomos Hepáticos/metabolismo , Oxirredução , Coelhos , Ratos , Saimiri , Ovinos , Espectrofotometria UltravioletaRESUMO
Julia olefination between alpha-halomethyl sulfones and a variety of aldehydes afforded alkenyl halides in good to excellent yields with high E/Z stereoselectivities. Sulfones were readily prepared in two or three steps from commercially available reagents in good yields. Optimization revealed that the nature of the solvent, the base, and the additive were crucial to obtain the desired alkenyl halides.
Assuntos
Alcenos/síntese química , Brometos/síntese química , Cloretos/síntese química , Aldeídos/química , Estereoisomerismo , Sulfonas/síntese química , Sulfonas/químicaRESUMO
A novel indole series of PGD2 receptor (DP receptor) antagonists is presented. Optimization of this series led to the identification of potent and selective DP receptor antagonists. In particular, antagonists 35 and 36 were identified with Ki values of 2.6 and 1.8 nM, respectively. These two antagonists are also potent in a DP functional assay where they inhibit the PGD2 induced cAMP production in platelet rich plasma with IC50 values of 7.9 and 8.6 nM, respectively. The structure-activity relationships of this indole series of DP receptor antagonists will also be discussed.
Assuntos
Indóis/química , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Indóis/síntese química , Estrutura Molecular , Receptores Imunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Safrol/análogos & derivados , Safrol/química , Relação Estrutura-AtividadeRESUMO
Tetrahydrogestrinone (18a-homo-pregna-4,9,11-trien-17beta-ol-3-one, THG) is an anabolic androgenic steroid sold to athletes as an undetectable performance enhancer. Being an unapproved substance, no legitimate in vivo human excretion studies could be performed to identify urinary markers of this doping agent. In vitro systems were used as an alternative approach to study the human metabolism of THG and the gestrinone analogue, which is a marketed drug. Incubations of both compounds in the presence of human hepatocytes led to formation of oxidative and glucuroconjugated metabolites. Microgram quantities of the major in vitro metabolites were biosynthesized using human hepatocytes, characterized by HPLC/MS/MS, and their structures elucidated by NMR. Due to high structure similarity, both THG and gestrinone had an analogous in vitro metabolic pathway leading to successive addition of a hydroxyl and a beta-glucuronic acid at C-18. This in vitro metabolite of gestrinone was consistent with a previously reported major but unknown human urinary metabolite. The structure of another metabolite of THG was proposed to be a glucuroconjugate of an oxidative product with a hydroxyl group most likely at C-16epsilon. In vitro information reported therein could significantly impact the identification of new urinary markers of THG for doping control purposes.