RESUMEN
Galectin-3 (Gal-3) is a carbohydrate binding protein that has been implicated in the development and progression of fibrotic diseases. Proof-of-principal animal models have demonstrated that inhibition of Gal-3 is a potentially viable pathway for the treatment of fibrosisâwith small molecule Gal-3 inhibitors advanced into clinical trials. We hereby report the discovery of novel galactose-based monosaccharide Gal-3 inhibitors comprising 2-methyl-4-phenyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (compound 20) and 4-phenyl-4H-1,2,4-triazole (compound 15). Notably, hindered rotation caused by steric interaction between the 3-thione and ortho-trifluoromethyl group of compounds 20, 21 induced formation of thermodynamically stable atropisomers. Distinct X-ray cocrystal structures of 20 and 21 were obtained, which clearly demonstrated that the configuration of 21 proscribes a key halogen bonding σ-hole interaction of 3-chloro with carbonyl oxygen of Gly182, thereby leading to significant loss in potency. Ultimately, 20 and 15 were evaluated in mouse pharmacokinetic studies, and both compounds exhibited oral exposures suitable for further in vivo assessment.
Asunto(s)
Galactosa , Galectina 3 , Triazoles , Triazoles/química , Triazoles/farmacología , Triazoles/síntesis química , Triazoles/farmacocinética , Galactosa/química , Galactosa/metabolismo , Animales , Humanos , Galectina 3/antagonistas & inhibidores , Galectina 3/metabolismo , Ratones , Relación Estructura-Actividad , Cristalografía por Rayos X , Tionas/química , Tionas/farmacología , Tionas/síntesis química , Tionas/farmacocinética , Proteínas Sanguíneas/metabolismo , Galectinas/antagonistas & inhibidores , Galectinas/metabolismo , Modelos MolecularesRESUMEN
RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease for which current treatment options only slow clinical progression. Previously, we identified a subset of patients with IPF with an accelerated disease course associated with fibroblast expression of Toll-Like Receptor 9 (TLR9) mediated by interactions with its ligand mitochondrial DNA (mtDNA). OBJECTIVES: We aimed to show that TLR9 activation induces fibroproliferative responses that are abrogated by its antagonism by using two commercially-available indirect inhibitors and a proprietary, selective direct small molecule inhibitor. METHODS: We employed two independent cohorts of patients with IPF, multiple in vitro fibroblast cell culture platforms, an in vivo mouse model, and an ex vivo human precision cut lung slices system to investigate the clinical and biologic significance of TLR9 in this disease. MEASUREMENTS AND MAIN RESULTS: In two independent IPF cohorts, plasma mtDNA activates TLR9 in a manner associated with the expression of MCP-1, IL-6, TNFα, and IP-10 and worsened transplant-free survival. Our cell culture platform showed that TLR9 mediates fibroblast activation via TGFß1 and stiff substrates, and that its antagonism, particularly direct inhibition, ameliorates this process, including production of these TLR9 associated pharmacodynamic endpoints. We further demonstrated that direct TLR9 inhibition mitigates these fibroproliferative responses in our in vivo and ex vivo models of pulmonary fibrosis. CONCLUSIONS: In this novel study, we found that direct TLR9 inhibition mitigates fibroproliferative responses in preclinical models of pulmonary fibrosis. Our work demonstrates the therapeutic potential of direct TLR9 antagonism in IPF and related fibrotic lung diseases.
RESUMEN
As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.
Asunto(s)
Galectina 3 , Monosacáridos , Animales , Humanos , Ratones , Benzotiazoles/química , Benzotiazoles/farmacología , Diseño de Fármacos , Galectina 3/antagonistas & inhibidores , Galectinas/antagonistas & inhibidores , Monosacáridos/química , Monosacáridos/farmacología , Oxígeno , AzufreRESUMEN
Efforts directed at improving potency and preparing structurally different TYK2 JH2 inhibitors from the first generation of compounds such as 1a led to the SAR study of new central pyridyl based analogs 2-4. The current SAR study resulted in the identification of 4h as a potent and selective TYK2 JH2 inhibitor with distinct structural differences from 1a. In this manuscript, the in vitro and in vivo profiles of 4h are described. The hWB IC50 of 4h was shown as 41 nM with 94% bioavailability in the mouse PK study.
Asunto(s)
Piridinas , TYK2 Quinasa , Ratones , Animales , Relación Estructura-Actividad , Piridinas/farmacologíaRESUMEN
Galectin-3 (Gal-3), a member of the ß-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.
Asunto(s)
Galectina 3 , Monosacáridos , Animales , Galectina 3/metabolismo , Galectinas , Humanos , Ligandos , RatonesRESUMEN
A search for structurally diversified Tyk2 JH2 ligands from 6 (BMS-986165), a pyridazine carboxamide-derived Tyk2 JH2 ligand as a clinical Tyk2 inhibitor currently in late development for the treatment of psoriasis, began with a survey of six-membered heteroaryl groups in place of the N-methyl triazolyl moiety in 6. The X-ray co-crystal structure of an early lead (12) revealed a potential new binding pocket. Exploration of the new pocket resulted in two frontrunners for a clinical candidate. The potential hydrogen bonding interaction with Thr599 in the pocket was achieved with a tertiary amide moiety, confirmed by the X-ray co-crystal structure of 29. When the diversity search was extended to nicotinamides, a single fluorine atom addition was found to significantly enhance the permeability, which directly led to the discovery of 7 (BMS-986202) as a clinical Tyk2 inhibitor that binds to Tyk2 JH2. The preclinical studies of 7, including efficacy studies in mouse models of IL-23-driven acanthosis, anti-CD40-induced colitis, and spontaneous lupus, will also be presented.
Asunto(s)
Ciclopropanos/farmacología , Descubrimiento de Drogas , Oxazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Animales , Catálisis , Cristalografía por Rayos X , Ciclopropanos/química , Humanos , Ratones , Oxazoles/química , Unión Proteica , Inhibidores de Proteínas Quinasas/química , Psoriasis/tratamiento farmacológico , Relación Estructura-Actividad , TYK2 Quinasa/metabolismoRESUMEN
In sharp contrast to a previously reported series of 6-anilino imidazopyridazine based Tyk2 JH2 ligands, 6-((2-oxo-N1-substituted-1,2-dihydropyridin-3-yl)amino)imidazo[1,2-b]pyridazine analogs were found to display dramatically improved metabolic stability. The N1-substituent on 2-oxo-1,2-dihydropyridine ring can be a variety of alkyl, aryl, and heteroaryl groups, but among them, 2-pyridyl provided much enhanced Caco-2 permeability, attributed to its ability to form intramolecular hydrogen bonds. Further structure-activity relationship studies at the C3 position led to the identification of highly potent and selective Tyk2 JH2 inhibitor 6, which proved to be highly effective in inhibiting IFNγ production in a rat pharmacodynamics model and fully efficacious in a rat adjuvant arthritis model.
RESUMEN
In search for prodrugs to address the issue of pH-dependent solubility and exposure associated with 1 (BMS-582949), a previously disclosed phase II clinical p38α MAP kinase inhibitor, a structurally novel clinical prodrug, 2 (BMS-751324), featuring a carbamoylmethylene linked promoiety containing hydroxyphenyl acetic acid (HPA) derived ester and phosphate functionalities, was identified. Prodrug 2 was not only stable but also water-soluble under both acidic and neutral conditions. It was effectively bioconverted into parent drug 1 in vivo by alkaline phosphatase and esterase in a stepwise manner, providing higher exposure of 1 compared to its direct administration, especially within higher dose ranges. In a rat LPS-induced TNFα pharmacodynamic model and a rat adjuvant arthritis model, 2 demonstrated similar efficacy to 1. Most importantly, it was shown in clinical studies that prodrug 2 was indeed effective in addressing the pH-dependent absorption issue associated with 1.
Asunto(s)
Organofosfatos/farmacología , Fenilacetatos/farmacología , Profármacos/química , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Administración Oral , Animales , Artritis Experimental/tratamiento farmacológico , Disponibilidad Biológica , Técnicas de Química Sintética , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Macaca fascicularis , Masculino , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Estructura Molecular , Organofosfatos/química , Fenilacetatos/química , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/química , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Solubilidad , Relación Estructura-ActividadRESUMEN
Investigation of various heterocyclic core isosteres of imidazopyrazines 1 & 2 yielded purine derivatives 3 & 8 as potent and selective BTK inhibitors. Subsequent SAR studies of the purine series led to the discovery of 20 as a leading compound. Compound 20 is very selective when screened against a panel of 400 kinases and is a potent inhibitor in cellular assays of human B cell function including B-Cell proliferation and CD86 cell surface expression and exhibited in vivo efficacy in a mouse PCA model. Its X-ray co-crystal structure with BTK shows that the high selectivity is gained from filling a BTK specific lipophilic pocket. However, physical and ADME properties leading to low oral exposure hindered further development.
Asunto(s)
Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Agammaglobulinemia Tirosina Quinasa , Animales , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/enzimología , Linfocitos B/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Ratones , Modelos Moleculares , Anafilaxis Cutánea Pasiva/efectos de los fármacos , Proteínas Tirosina Quinasas/metabolismo , RatasRESUMEN
A series of carbamoylmethylene linked prodrugs of 1 (BMS-582949), a clinical p38α inhibitor, were synthesized and evaluated. Though the phosphoryloxymethylene carbamates (3, 4, and 5) and α-aminoacyloxymethylene carbamates (22, 23, and 26) were found unstable at neutral pH values, fumaric acid derived acyloxymethylene carbamates (2, 28, and 31) were highly stable under both acidic and neutral conditions. Prodrugs 2 and 31 were also highly soluble at both acidic and neutral pH values. At a solution dose of 14.2mpk (equivalent to 10mpk of 1), 2 gave essentially the same exposure of 1 compared to dosing 10mpk of 1 itself. At a suspension dose of 142mpk (equivalent to 100mpk of 1), 2 demonstrated that it could overcome the solubility issue associated with 1 and provide a much higher exposure of 1. To our knowledge, the unique type of prodrugs like 2, 28, and 31 was not reported in the past and could represent a novel prodrug approach for secondary amides, a class of molecules frequently identified as drug candidates.
Asunto(s)
Dacarbazina/análogos & derivados , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Pirroles/farmacología , Triazinas/farmacología , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Dacarbazina/química , Relación Dosis-Respuesta a Droga , Concentración de Iones de Hidrógeno , Modelos Moleculares , Estructura Molecular , Profármacos/administración & dosificación , Profármacos/síntesis química , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/síntesis química , Pirroles/administración & dosificación , Pirroles/síntesis química , Ratas , Solubilidad , Relación Estructura-Actividad , Temperatura , Triazinas/administración & dosificación , Triazinas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
The radiation spectrum of pyrotechnics' burning flame was analyzed using transient spectrum radiometer. The working principle of multi-spectral thermometry was described. Combined with the radiation spectrum of pyrotechnics' burning flame, the multi-spectral thermometer system was designed which had twelve working channels. The tester can choose the right working channels to calculate according to the radiation spectrum of the flame to be tested. The system is composed by optics part, electronic part, data acquisition part and data processing part. In this paper, the emissive power of black powder's flame has been tested using the multi-spectral thermometer system. The burning flame temperature-time curve was showed after iteration calculation Experiments indicate that the multi-spectral thermometer system can be well used to measure the flame temperature of pyrotechnics based on analyzing the emissive power when choosing the right working channels. This method lays a foundation for the research of combustion output characteristics of pyrotechnics.
RESUMEN
The discovery and characterization of 7k (BMS-582949), a highly selective p38α MAP kinase inhibitor that is currently in phase II clinical trials for the treatment of rheumatoid arthritis, is described. A key to the discovery was the rational substitution of N-cyclopropyl for N-methoxy in 1a, a previously reported clinical candidate p38α inhibitor. Unlike alkyl and other cycloalkyls, the sp(2) character of the cyclopropyl group can confer improved H-bonding characteristics to the directly substituted amide NH. Inhibitor 7k is slightly less active than 1a in the p38α enzymatic assay but displays a superior pharmacokinetic profile and, as such, was more effective in both the acute murine model of inflammation and pseudoestablished rat AA model. The binding mode of 7k with p38α was confirmed by X-ray crystallographic analysis.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Pirroles/síntesis química , Triazinas/síntesis química , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/farmacología , Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/tratamiento farmacológico , Disponibilidad Biológica , Células CACO-2 , Cristalografía por Rayos X , Femenino , Humanos , Enlace de Hidrógeno , Técnicas In Vitro , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Conformación Molecular , Unión Proteica , Pirroles/farmacocinética , Pirroles/farmacología , Ratas , Ratas Endogámicas Lew , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-Actividad , Triazinas/farmacocinética , Triazinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Rational design, synthesis, and SAR studies of a novel class of benzothiazole based inhibitors of p38alpha MAP kinase are described. The issue of metabolic instability associated with vicinal phenyl, benzo[d]thiazol-6-yl oxazoles/imidazoles was addressed by the replacement of the central oxazole or imidazole ring with an aminopyrazole system. The proposed binding mode of this new class of p38alpha inhibitors was confirmed by X-ray crystallographic studies of a representative inhibitor (6a) bound to the p38alpha enzyme.
Asunto(s)
Benzotiazoles/química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/farmacología , Animales , Células Cultivadas/efectos de los fármacos , Células Cultivadas/enzimología , Cristalografía por Rayos X , Humanos , Lipopolisacáridos/farmacología , Ratones , Microsomas/efectos de los fármacos , Microsomas/enzimología , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Estructura Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity, and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 3 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo and was previously reported to reduce lung inflammation in a mouse model of ovalbumin induced allergy/asthma.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Sulfuros/síntesis química , Sulfuros/farmacología , Tiazoles/síntesis química , Tiazoles/farmacología , Animales , Asma/patología , Células Cultivadas , Humanos , Hipersensibilidad/patología , Células Jurkat/efectos de los fármacos , Ratones , Neumonía/patología , Relación Estructura-ActividadRESUMEN
A series of structurally novel aminothiazole based small molecule inhibitors of Itk were prepared to elucidate their structure-activity relationships (SARs), selectivity and cell activity in inhibiting IL-2 secretion in a Jurkat T-cell assay. Compound 2 is identified as a potent and selective Itk inhibitor which inhibits anti-TCR antibody induced IL-2 production in mice in vivo.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Tiazoles/farmacología , Animales , Anticuerpos Monoclonales/efectos de los fármacos , Anticuerpos Monoclonales/farmacología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Interleucina-2/biosíntesis , Células Jurkat , Ratones , Estructura Molecular , Receptores de Antígenos de Linfocitos T/efectos de los fármacos , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/químicaRESUMEN
A novel class of 5-cyanopyrimidine-based inhibitors of p38alpha MAP kinase has been investigated. Analogues optimized through SAR iterations display low nanomolar enzymatic and cellular activity. The in vivo efficacy of this class of p38 inhibitors was demonstrated by 3a and 3b (>50% reduction in TNF levels when orally dosed at 5 mg/kg, 5 h prior to LPS administration in an acute murine model of inflammation). For 3a and 3b, the previously identified N-methoxybenzamide moiety (1) was replaced with N-(isoxazol-3-yl)benzamide, thereby providing increased metabolic stability. Cyanopyrimidine 3a demonstrated 100% oral bioavailability in mouse. High p38 kinase selectivity versus over 20 kinases was observed for analogue 3b. Direct hydrogen bonding of the cyano nitrogen of the 5-cyanopyrimidine core to the backbone NH of Met109 was confirmed by X-ray crystallographic analysis of 3a bound to p38alpha.
Asunto(s)
Antiinflamatorios no Esteroideos/síntesis química , Benzamidas/síntesis química , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Nitrilos/síntesis química , Pirimidinas/síntesis química , Administración Oral , Animales , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/farmacología , Benzamidas/química , Benzamidas/farmacología , Disponibilidad Biológica , Células Cultivadas , Cristalografía por Rayos X , Femenino , Humanos , Técnicas In Vitro , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/química , Modelos Moleculares , Nitrilos/química , Nitrilos/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Ratas , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Nonreceptor protein tyrosine kinases including Lck, ZAP-70, and Itk play essential roles in T-cell receptor (TCR) signaling. Gene knockout studies have revealed that mice lacking these individual kinases exhibit various degrees of immunodeficiency; however, highly selective small molecule inhibitors of these kinases as potential immunosuppressive agents have not been identified. Here we discovered two novel compounds, BMS-488516 and BMS-509744, that potently and selectively inhibit Itk kinase activity. The compounds reduce TCR-induced functions including PLCgamma1 tyrosine phosphorylation, calcium mobilization, IL-2 secretion, and T-cell proliferation in vitro in both human and mouse cells. The inhibitors suppress the production of IL-2 induced by anti-TCR antibody administered to mice. BMS-509744 also significantly diminishes lung inflammation in a mouse model of ovalbumin-induced allergy/asthma. Our findings represent the first description of selective inhibitors to probe human Itk function and its associated pathway, and support the hypothesis that Itk is a therapeutic target for immunosuppressive and inflammatory diseases.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores Enzimáticos/farmacología , Pulmón/enzimología , Pulmón/patología , Activación de Linfocitos/efectos de los fármacos , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimología , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Línea Celular Tumoral , Inhibidores Enzimáticos/administración & dosificación , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/farmacología , Interleucina-2/antagonistas & inhibidores , Interleucina-2/biosíntesis , Células Jurkat , Pulmón/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidores , Receptores de Antígenos de Linfocitos T/fisiología , Hipersensibilidad Respiratoria/enzimología , Hipersensibilidad Respiratoria/patología , Hipersensibilidad Respiratoria/prevención & control , Linfocitos T/metabolismoRESUMEN
A series of structurally novel benzothiazole based small molecule inhibitors of p56(lck) was prepared to elucidate their structure-activity relationships (SAR), selectivity and cell activity in the T-cell proliferation assay. BMS-350751 (2) and BMS-358233 (3) are identified as potent Lck inhibitors with excellent cellular activities against T-cell proliferation.
Asunto(s)
Anilidas/síntesis química , Anilidas/farmacología , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/antagonistas & inhibidores , Tiazoles/síntesis química , Tiazoles/farmacología , División Celular/efectos de los fármacos , Cristalografía por Rayos X , Humanos , Modelos Moleculares , Conformación Proteica , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacos , Linfocitos T/enzimologíaRESUMEN
A series of heterocyclic replacements for the central diamide moiety of 1, a potent small molecule inhibitor of inosine monophosphate dehydrogenase (IMPDH) were explored The synthesis and the structure-activity relationships (SARs), derived from in vitro studies, for these new series of inhibitors is given.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , IMP Deshidrogenasa/antagonistas & inhibidores , Humanos , Técnicas In Vitro , Indicadores y Reactivos , Ligandos , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Modelos Moleculares , Conformación Molecular , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A series of novel amide-based small molecule inhibitors of inosine monophosphate dehydrogenase (IMPDH) was explored. The synthesis and the structure-activity relationships (SARs) derived from in vitro studies are described.