RESUMEN
Previous studies have identified a series of imidazo[1,2-a]pyridine (IZP) derivatives as potent allosteric inhibitors of HIV-1 integrase (ALLINIs) and virus infection in cell culture. However, IZPs were also found to be relatively potent activators of the pregnane-X receptor (PXR), raising the specter of induction of CYP-mediated drug disposition pathways. In an attempt to modify PXR activity without affecting anti-HIV-1 activity, rational structure-based design and modeling approaches were used. An X-ray cocrystal structure of (S,S)-1 in the PXR ligand binding domain (LBD) allowed an examination of the potential of rational structural modifications designed to abrogate PXR. The introduction of bulky basic amines at the C-8 position provided macrocyclic IZP derivatives that displayed potent HIV-1 inhibitory activity in cell culture with no detectable PXR transactivation at the highest concentration tested.
Asunto(s)
Fármacos Anti-VIH/farmacología , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , Compuestos Macrocíclicos/farmacología , Receptor X de Pregnano/antagonistas & inhibidores , Regulación Alostérica/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Fármacos Anti-VIH/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/química , Humanos , Compuestos Macrocíclicos/síntesis química , Compuestos Macrocíclicos/química , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Receptor X de Pregnano/metabolismo , Relación Estructura-Actividad , Replicación Viral/efectos de los fármacosRESUMEN
Adaptor protein 2-associated kinase 1 (AAK1) is a serine/threonine kinase that was identified as a therapeutic target for the potential treatment of neuropathic pain. Inhibition of AAK1 in the central nervous system, particularly within the spinal cord, was found to be the relevant site for achieving an antinociceptive effect. We previously reported that compound 7 is a brain-penetrant, AAK1 inhibitor that showed efficacy in animal models for neuropathic pain. One approach we took to improve upon the potency of 7 involved tying the amide back into the neighboring phenyl ring to form a bicyclic heterocycle. Investigation of the structure-activity relationships (SARs) of substituents on the resultant quinazoline and quinoline ring systems led to the identification of (S)-31, a brain-penetrant, AAK1-selective inhibitor with improved enzyme and cellular potency compared to 7. The synthesis, SAR, and in vivo evaluation of a series of quinazoline and quinoline-based AAK1 inhibitors are described herein.
Asunto(s)
Neuralgia , Quinolinas , Amidas/farmacología , Amidas/uso terapéutico , Animales , Neuralgia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Quinolinas/farmacología , Quinolinas/uso terapéutico , Relación Estructura-ActividadRESUMEN
The synthesis, evaluation, and structure-activity relationships of a class of γ-lactam 1,3-diaminopropan-2-ol transition-state isostere inhibitors of BACE are discussed. Two strategies for optimizing lead compound 1a are presented. Reducing the overall size of the inhibitors resulted in the identification of γ-lactam 1i, whereas the introduction of conformational constraint on the prime-side of the inhibitor generated compounds such as the 3-hydroxypyrrolidine inhibitor 28n. The full in vivo profile of 1i in rats and 28n in Tg 2576 mice is presented.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Lactamas/química , Lactamas/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/enzimología , Animales , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Lactamas/síntesis química , Lactamas/farmacocinética , Ratones , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 µM, %F=18), are reported.
Asunto(s)
Activación Enzimática/efectos de los fármacos , Hepacivirus/enzimología , Compuestos Heterocíclicos/síntesis química , Compuestos Heterocíclicos/farmacología , Indoles/química , Proteínas no Estructurales Virales/antagonistas & inhibidores , Diseño de Fármacos , Compuestos Heterocíclicos/química , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Heterocyclic replacement of the isophthalamide phenyl ring in hydroxyethylamine (HEA) BACE-1 inhibitors was explored. A variety of indole-1,3-dicarboxamide HEAs exhibited potent BACE-1 enzyme inhibition, but displayed poor cellular activity. Improvements in cellular activity and aspartic protease selectivity were observed for 7-azaindole-1,3-dicarboxamide HEAs. A methylprolinol-bearing derivative (10n) demonstrated robust reductions in rat plasma Aß levels, but did not lower rat brain Aß due to poor central exposure. The same analog exhibited a high efflux ratio in a bidirectional Caco-2 assay and was likely a substrate of the efflux transporter P-glycoprotein. X-ray crystal structures are reported for two indole HEAs in complex with BACE-1.
Asunto(s)
Aminas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Indoles/síntesis química , Inhibidores de Proteasas/química , Piridinas/síntesis química , Aminas/síntesis química , Aminas/farmacología , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/sangre , Animales , Ácido Aspártico Endopeptidasas/metabolismo , Sitios de Unión , Cristalografía por Rayos X , Indoles/química , Indoles/farmacología , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Estructura Terciaria de Proteína , Piridinas/química , Piridinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
The synthesis, evaluation, and structure-activity relationships of a set of related constrained diaminopropane inhibitors of BACE-1 are described. The full in vivo profile of an optimized inhibitor in both normal and P-gp deficient mice is compared with data generated in normal rats.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Diaminas/química , Diaminas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Cristalografía por Rayos X , Diaminas/síntesis química , Diaminas/farmacocinética , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Ratones , Ratones Noqueados , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
Derived from the HTS hit 1, a series of hydroxyisoquinolines was discovered as potent and selective 11ß-HSD1 inhibitors with good cross species activity. Optimization of substituents at the 1 and 4 positions of the isoquinoline group in addition to the core modifications, with a special focus on enhancing metabolic stability and aqueous solubility, resulted in the identification of several compounds as potent advanced leads.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Isoquinolinas/química , Isoquinolinas/farmacología , Animales , Línea Celular , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Inhibidores Enzimáticos/farmacocinética , Humanos , Isoquinolinas/farmacocinética , Ratones , Ratones Endogámicos BALB C , Relación Estructura-ActividadRESUMEN
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
BMS-823778 (2), a 1,2,4-triazolopyridinyl-methanol derived analog, was identified as a potent and selective inhibitor of human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD-1) enzyme (IC50 = 2.3 nM) with >10,000-fold selectivity over 11ß-HSD-2. Compound 2 exhibits robust acute pharmacodynamic effects in cynomolgus monkeys (ED50 = 0.6 mg/kg) and in diet-induced obese (DIO) mice (ED50 = 34 mg/kg). Compound 2 also showed excellent inhibition in an ex vivo adipose DIO mouse model (ED50 = 5.2 mg/kg). Oral bioavailability ranges from 44% to 100% in preclinical species. Its favorable development properties, pharmacokinetics, high adipose-to-plasma concentration ratio, and preclinical pharmacology profile have prompted the evaluation of 2 for the treatment of type 2 diabetes and metabolic syndrome in phase 2 clinical trials.
RESUMEN
BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) enzyme (IC50 3.0 nM) with >10000-fold selectivity over human 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11ß-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.
Asunto(s)
11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/antagonistas & inhibidores , Adamantano/análogos & derivados , Azetidinas/farmacología , Inhibidores Enzimáticos/farmacología , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/química , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 1/metabolismo , Actinas/antagonistas & inhibidores , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacología , Administración Oral , Animales , Azetidinas/administración & dosificación , Azetidinas/química , Disponibilidad Biológica , Cristalografía por Rayos X , Perros , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/química , Femenino , Semivida , Humanos , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Concentración 50 Inhibidora , Macaca fascicularis , Masculino , Ratones Obesos , Ratas , Relación Estructura-ActividadRESUMEN
NMR spectroscopy was used to characterize the hepatitis C virus (HCV) NS3 protease in a complex with the 24 residue peptide cofactor from NS4A and a boronic acid inhibitor, Ac-Asp-Glu-Val-Val-Pro-boroAlg-OH. Secondary-structure information, NOE constraints between protease and cofactor, and hydrogen-deuterium exchange rates revealed that the cofactor was an integral strand in the N-terminal beta-sheet of the complex as observed in X-ray crystal structures. Based upon chemical-shift perturbations, inhibitor-protein NOEs, and the protonation state of the catalytic histidine, the boronic acid inhibitor was bound in the substrate binding site as a transition state mimic. In the absence of cofactor, the inhibitor had a lower affinity for the protease. Although the inhibitor binds in the same location, differences were observed at the catalytic site of the protease.
Asunto(s)
Ácidos Borónicos/química , Proteínas Portadoras/química , Hepacivirus/enzimología , Inhibidores de Proteasas/química , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Proteínas Virales/química , Sitios de Unión , Ácidos Borónicos/farmacología , Cristalografía por Rayos X , Humanos , Péptidos y Proteínas de Señalización Intracelular , Espectroscopía de Resonancia Magnética , Inhibidores de Proteasas/farmacologíaRESUMEN
The human pregnane X receptor (PXR) is a promiscuous nuclear receptor that functions as a sensor to a wide variety of xenobiotics and regulates expression of several drug metabolizing enzymes and transporters. We have generated "Adnectins", derived from 10th fibronectin type III domain ((10)Fn3), that target the PXR ligand binding domain (LBD) interactions with the steroid receptor co-activator-1 (SRC-1) peptide, displacing SRC-1 binding. Adnectins are structurally homologous to the immunoglobulin superfamily. Three different co-crystal structures of PXR LBD with Adnectin-1 and CCR1 (CC chemokine receptor-1) antagonist Compound-1 were determined. This structural information was used to modulate PXR affinity for a related CCR1 antagonist compound that entered into clinical trials for rheumatoid arthritis. The structures of PXR with Adnectin-1 reveal specificity of Adnectin-1 in not only targeting the interface of the SRC-1 interactions but also engaging the same set of residues that are involved in binding of SRC-1 to PXR. Substituting SRC-1 with Adnectin-1 does not alter the binding conformation of Compound-1 in the ligand binding pocket. The structure also reveals the possibility of using Adnectins as crystallization chaperones to generate structures of PXR with compounds of interest.
Asunto(s)
Coactivador 1 de Receptor Nuclear/química , Receptores CCR1/antagonistas & inhibidores , Receptores de Esteroides/química , Urea/análogos & derivados , Valina/análogos & derivados , Secuencia de Aminoácidos , Sitios de Unión , Cristalografía por Rayos X , Humanos , Lignanos/metabolismo , Modelos Moleculares , Datos de Secuencia Molecular , Receptor X de Pregnano , Unión Proteica , Estructura Terciaria de Proteína , Receptores CCR1/metabolismo , Alineación de Secuencia , Resonancia por Plasmón de Superficie , Urea/química , Urea/metabolismo , Urea/farmacología , Valina/química , Valina/metabolismo , Valina/farmacologíaRESUMEN
Small alkyl groups and spirocyclic-aromatic rings directly attached to the left side and right side of the 1,2,4-triazolopyridines (TZP), respectively, were found to be potent and selective inhibitors of human 11ß-hydroxysteroid dehydrogenase-type 1 (11ß-HSD-1) enzyme. 3-(1-(4-Chlorophenyl)cyclopropyl)-8-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridine (9f) was identified as a potent inhibitor of the 11ß-HSD-1 enzyme with reduced Pregnane-X receptor (PXR) transactivation activity. The binding orientation of this TZP series was revealed by X-ray crystallography structure studies.
RESUMEN
High-affinity, functionally potent, urea-based antagonists of CCR1 have been discovered. Modulation of PXR transactivation has revealed the selective and orally bioavailable CCR1 antagonist BMS-817399 (29), which entered clinical trials for the treatment of rheumatoid arthritis.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Descubrimiento de Drogas , Piperidinas/farmacología , Receptores CCR1/antagonistas & inhibidores , Urea/análogos & derivados , Valina/análogos & derivados , Animales , Disponibilidad Biológica , Ensayos Clínicos Fase II como Asunto , Células Hep G2 , Humanos , Masculino , Microsomas Hepáticos/metabolismo , Modelos Moleculares , Piperidinas/metabolismo , Piperidinas/farmacocinética , Piperidinas/uso terapéutico , Receptor X de Pregnano , Conformación Proteica , Receptores CCR1/química , Receptores CCR1/metabolismo , Receptores de Esteroides/metabolismo , Especificidad de la Especie , Urea/metabolismo , Urea/farmacocinética , Urea/farmacología , Urea/uso terapéutico , Valina/metabolismo , Valina/farmacocinética , Valina/farmacología , Valina/uso terapéuticoRESUMEN
Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.
Asunto(s)
Antivirales/farmacología , Benzazepinas/farmacología , Inhibidores Enzimáticos/farmacología , Indoles/farmacología , Proteínas no Estructurales Virales/antagonistas & inhibidores , Regulación Alostérica , Animales , Antivirales/química , Antivirales/farmacocinética , Benzazepinas/química , Benzazepinas/farmacocinética , Perros , Descubrimiento de Drogas , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacocinética , Humanos , Indoles/química , Indoles/farmacocinética , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Modelos Moleculares , Ratas , Relación Estructura-ActividadRESUMEN
This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-π interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Aß levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Aß levels were not obtained.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Guanidinas/síntesis química , Bibliotecas de Moléculas Pequeñas , Secretasas de la Proteína Precursora del Amiloide/química , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animales , Ácido Aspártico Endopeptidasas/química , Encéfalo/metabolismo , Línea Celular , Cristalografía por Rayos X , Guanidinas/farmacocinética , Guanidinas/farmacología , Humanos , Isoxazoles/síntesis química , Isoxazoles/farmacocinética , Isoxazoles/farmacología , Modelos Moleculares , Estructura Molecular , Mutación , Fragmentos de Péptidos/metabolismo , Unión Proteica , Ensayo de Unión Radioligante , Ratas , Técnicas de Síntesis en Fase Sólida , Soluciones , Relación Estructura-ActividadRESUMEN
Amyloid precursor protein (APP) cleaving enzyme (BACE) is the enzyme responsible for beta-site cleavage of APP, leading to the formation of the amyloid-beta peptide that is thought to be pathogenic in Alzheimer's disease (AD). Hence, BACE is an attractive pharmacological target, and numerous research groups have begun searching for potent and selective inhibitors of this enzyme as a potential mechanism for therapeutic intervention in AD. The mature enzyme is composed of a globular catalytic domain that is N-linked glycosylated in mammalian cells, a single transmembrane helix that anchors the enzyme to an intracellular membrane, and a short C-terminal domain that extends outside the phospholipid bilayer of the membrane. Here we have compared the substrate and active site-directed inhibitor binding properties of several recombinant constructs of human BACE. The constructs studied here address the importance of catalytic domain glycosylation state, inclusion of domains other than the catalytic domain, and incorporation into a membrane bilayer on the interactions of the enzyme active site with peptidic ligands. We find no significant differences in ligand binding properties among these various constructs. These data demonstrate that the nonglycosylated, soluble catalytic domain of BACE faithfully reflects the ligand binding properties of the full-length mature enzyme in its natural membrane environment. Thus, the use of the nonglycosylated, soluble catalytic domain of BACE is appropriate for studies aimed at understanding the determinants of ligand recognition by the enzyme active site.