RESUMEN
A novel class of pyridinyl aminohydantoins was designed and prepared as highly potent BACE1 inhibitors. Compound (S)-4g showed excellent potency with IC(50) of 20 nM for BACE1. X-ray crystallography indicated that the interaction between pyridine nitrogen and the tryptophan Trp76 was a key feature in the S2' region of the enzyme that contributed to increased potency.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Hidantoínas/farmacología , Piridinas/farmacología , Secretasas de la Proteína Precursora del Amiloide/química , Ácido Aspártico Endopeptidasas/química , Cristalografía por Rayos X , Humanos , Hidantoínas/química , Modelos Moleculares , Unión Proteica , Piridinas/química , Relación Estructura-ActividadRESUMEN
The identification of small molecule aminohydantoins as potent and selective human beta-secretase inhibitors is reported. These analogues exhibit low nannomolar potency for BACE1, show comparable activity in a cell-based (ELISA) assay, and demonstrate >100x selectivity for the other structurally related aspartyl proteases BACE2, cathepsinD, renin, and pepsin. On the basis of the cocrystal structure of the HTS-hit 2 in the BACE1 active site and by use of a structure-based drug design approach, we methodically explored the comparatively large binding pocket of the BACE1 enzyme and identified key interactions between the ligand and the protein that contributed to the affinity. One of the more potent compounds, (S)-55, displayed an IC(50) value for BACE1 of 10 nM and exhibited comparable cellular activity (EC(50) = 20 nM) in the ELISA assay. Acute oral administration of (S)-55 at 100 mg/kg resulted in a 69% reduction of plasma A beta(40) at 8 h in a Tg2576 mouse (p < 0.001).
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Diseño de Fármacos , Hidantoínas/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/síntesis química , Animales , Células CHO , Cricetinae , Cricetulus , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno , Ratones , Mitocondrias/efectos de los fármacos , Modelos Químicos , Estructura Molecular , Inhibidores de Proteasas/farmacología , Relación Estructura-ActividadRESUMEN
Piperidinyl diphenylsulfonyl sulfonamides are a novel class of molecules that have inhibitory binding affinity for sFRP-1. As a secreted protein sFRP-1 inhibits the function of the secreted Wnt glycoprotein. Therefore, as inhibitors of sFRP-1 these small molecules facilitate the Wnt/beta-catenin canonical signaling pathway. Details of the structure-activity relationships and biological activity of this structural class of compounds will be discussed.
Asunto(s)
Glicoproteínas/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Sulfonamidas/química , Sulfonamidas/farmacología , Proteínas Wnt/metabolismo , Animales , Línea Celular Tumoral , Glicoproteínas/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular , Ratones , Microsomas Hepáticos/metabolismo , Técnicas de Cultivo de Órganos , Osteogénesis/efectos de los fármacos , Ratas , Cráneo/citología , Cráneo/efectos de los fármacos , Relación Estructura-Actividad , beta Catenina/metabolismoRESUMEN
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.
Asunto(s)
Osteogénesis/efectos de los fármacos , Piperidinas/farmacología , Pirimidinas/farmacología , Proteínas Wnt/agonistas , beta Catenina/agonistas , Animales , Dominio Catalítico , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3 beta , Humanos , Ratones , Modelos Moleculares , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Pirimidinas/administración & dosificación , Pirimidinas/farmacocinética , Ratas , Transducción de Señal/efectos de los fármacos , Proteínas Wnt/metabolismo , beta Catenina/metabolismoRESUMEN
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.
Asunto(s)
Bencimidazoles/síntesis química , Quinoxalinas/síntesis química , Receptores LHRH/antagonistas & inhibidores , Administración Oral , Animales , Bencimidazoles/química , Bencimidazoles/farmacología , Unión Competitiva , Disponibilidad Biológica , Semivida , Humanos , Técnicas In Vitro , Hormona Luteinizante/sangre , Masculino , Microsomas Hepáticos/metabolismo , Orquiectomía , Hipófisis/efectos de los fármacos , Hipófisis/metabolismo , Quinoxalinas/química , Quinoxalinas/farmacología , Ensayo de Unión Radioligante , Ratas , Relación Estructura-ActividadRESUMEN
The diphenylsulfonyl sulfonamide scaffold represented by 1 (WAY-316606) are small molecule inhibitors of the secreted protein sFRP-1, an endogenous antagonist of the secreted glycoprotein Wnt. Modulators of the Wnt pathway have been proposed as anabolic agents for the treatment of osteoporosis or other bone-related disorders. Details of the structure-activity relationships and biological activity from the first structural class of this scaffold will be discussed.
Asunto(s)
Piperidinas/química , Proteínas/antagonistas & inhibidores , Proteínas/metabolismo , Transducción de Señal/efectos de los fármacos , Sulfanilamidas/síntesis química , Sulfanilamidas/farmacología , Proteínas Wnt/metabolismo , Animales , Línea Celular Tumoral , Genes Reporteros/genética , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular , Isomerismo , Ratones , Estructura Molecular , Unión Proteica , Cráneo/efectos de los fármacos , Relación Estructura-Actividad , Sulfanilamidas/química , Proteínas Wnt/genéticaRESUMEN
A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.
Asunto(s)
Amidas/química , Bencimidazoles/química , Ácidos Carboxílicos/química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Microsomas Hepáticos/metabolismo , Proteínas Tirosina Quinasas/química , Animales , Bencimidazoles/síntesis química , Ácidos Carboxílicos/síntesis química , Cristalografía por Rayos X , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Concentración 50 Inhibidora , Ratones , Modelos Químicos , Conformación Molecular , Relación Estructura-ActividadRESUMEN
Rapamycin is an immunosuppressive immunophilin ligand reported as having neurotrophic activity. We show that modification of rapamycin at the mammalian target of rapamycin (mTOR) binding region yields immunophilin ligands, WYE-592 and ILS-920, with potent neurotrophic activities in cortical neuronal cultures, efficacy in a rodent model for ischemic stroke, and significantly reduced immunosuppressive activity. Surprisingly, both compounds showed higher binding selectivity for FKBP52 versus FKBP12, in contrast to previously reported immunophilin ligands. Affinity purification revealed two key binding proteins, the immunophilin FKBP52 and the beta1-subunit of L-type voltage-dependent Ca(2+) channels (CACNB1). Electrophysiological analysis indicated that both compounds can inhibit L-type Ca(2+) channels in rat hippocampal neurons and F-11 dorsal root ganglia (DRG)/neuroblastoma cells. We propose that these immunophilin ligands can protect neurons from Ca(2+)-induced cell death by modulating Ca(2+) channels and promote neurite outgrowth via FKBP52 binding.
Asunto(s)
Canales de Calcio/química , Sirolimus/química , Proteínas de Unión a Tacrolimus/química , Animales , Calcio/metabolismo , Electrofisiología/métodos , Humanos , Inmunofilinas/metabolismo , Inmunosupresores/farmacología , Ligandos , Modelos Químicos , Neuritas/metabolismo , Neuroblastoma/metabolismo , Neuronas/metabolismo , Técnicas de Placa-Clamp , Unión Proteica , Ratas , Accidente Cerebrovascular/metabolismoRESUMEN
1-Aminoethyl-3-arylsulfonyl-1H-indoles 1 are 5-HT(6) receptor ligands with modest activity in a 5-HT(6) cyclase assay. Introduction of an additional nitrogen in the indole ring provides 1-aminoethyl-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines 2 with both enhanced 5-HT(6) affinity and cyclase activity, many acting as 5-HT(6) agonists. We constrained the basic side chain as part of a ring to make 1-(azacyclyl)-3-arylsulfonyl-1H-pyrrolo[2,3-b]pyridines incorporating a pyrrolidinyl 3 or piperidinyl 4 ring system. Preparation of compounds 3 and 4 required synthesis of the key intermediates, 1-(pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 7 and 1-(piperidin-3-yl)-1H-pyrrolo[2,3-b]pyridines 8, respectively. Intermediates 7 were prepared through alkylation of 7-azaindole while the intermediates 8 required an alternate synthesis. The compounds of both series 3 and 4 were shown to have high binding affinities for the 5-HT(6) receptor. The in vitro functional activity at the 5-HT(6) receptor varied depending on various functionalities including the selection of the arylsulfonyl, the substitution on the arylsulfonyl group, the ring size, and the substitution on the basic amine moiety producing either 5-HT(6) receptor agonists or antagonists.
Asunto(s)
Piridinas/farmacología , Receptores de Serotonina/química , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Unión Competitiva , Células HeLa/efectos de los fármacos , Humanos , Ligandos , Estructura Molecular , Piridinas/síntesis química , Piridinas/química , Receptores de Serotonina/metabolismo , Antagonistas de la Serotonina/síntesis química , Antagonistas de la Serotonina/química , Agonistas de Receptores de Serotonina/síntesis química , Agonistas de Receptores de Serotonina/química , Relación Estructura-ActividadRESUMEN
Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.
Asunto(s)
Modelos Moleculares , Inhibidores de Proteínas Quinasas/síntesis química , Sulfonamidas/síntesis química , Proteínas Quinasas p38 Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Quinasas p38 Activadas por Mitógenos/química , Animales , Sitios de Unión , Disponibilidad Biológica , Simulación por Computador , Cristalografía por Rayos X , Diseño de Fármacos , Lipopolisacáridos/farmacología , Masculino , Ratones , Niacinamida/análogos & derivados , Niacinamida/síntesis química , Niacinamida/química , Niacinamida/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Sulfonamidas/química , Sulfonamidas/farmacología , Tiofenos/síntesis química , Tiofenos/química , Tiofenos/farmacología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
An uHTS campaign was performed to identify selective inhibitors of PKC-theta. Initial triaging of the hit set based on selectivity and historical analysis led to the identification of 2,4-diamino-5-nitropyrimidines as potent and selective PKC-theta inhibitors. A homology model and initial SAR is presented demonstrating that a 2-arylalkylamino substituent in conjunction with suitable 4-diamino substituent are essential for achieving selectivity over many kinases. Additional hit to lead profiling is presented on selected compounds.
Asunto(s)
Isoenzimas/antagonistas & inhibidores , Proteína Quinasa C/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/química , Pirimidinas/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/enzimología , Linfocitos T CD4-Positivos/inmunología , Humanos , Interleucina-2/metabolismo , Modelos Moleculares , Estructura Molecular , Conformación Proteica , Proteína Quinasa C-theta , Relación Estructura-ActividadRESUMEN
Employing phenylmalonitrile dianion chemistry, a large number of analogues of MEK inhibitor lead SH053 (IC(50)=140 nM) were rapidly synthesized leading to single digit nM inhibitors, displaying submicromolar AP-1 transcription inhibition in COS-7 cells. Compound 41, exhibiting a MEK IC(50)=12 nM showed ip activity in a TPA-induced ear edema model with an ED(50)=5 mg/kg.
Asunto(s)
Butadienos/síntesis química , Química Farmacéutica/métodos , Inhibidores Enzimáticos/síntesis química , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Nitrilos/síntesis química , Animales , Células COS , Chlorocebus aethiops , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Relación Estructura-ActividadRESUMEN
Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[[4-(4-quinolinyloxymethyl)anilinyl]carbonyl]-1-cyclohexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl]-5-piperidinecarboxamide] exhibited an IC(50) value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs.
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Succinatos/síntesis química , Proteínas ADAM , Proteína ADAM17 , Diseño de Fármacos , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Cinética , Modelos Moleculares , Conformación Molecular , Relación Estructura-Actividad , Succinatos/química , Succinatos/farmacologíaRESUMEN
Rational design based on the broad spectrum MMP inhibitor CGS 27023A led to the identification of a novel series of cyclic succinate TACE inhibitors. As a mixture of two enantiomers, the lead compound 17b exhibited potent enzyme activity (IC(50)=8 nM) in the inhibition of porcine TNF-alpha converting enzyme (pTACE) and excellent selectivity over aggrecanase and MMP-1, -2 and -9.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Succinatos/farmacología , Proteínas ADAM , Proteína ADAM17 , Diseño de Fármacos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Ácidos Hidroxámicos/farmacología , Modelos Moleculares , Conformación Molecular , Inhibidores de Proteasas/farmacología , Pirazinas/farmacología , Relación Estructura-Actividad , Succinatos/síntesis química , Succinatos/química , Sulfonamidas/farmacologíaRESUMEN
New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.
Asunto(s)
Acetamidas/química , Acetamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Metaloendopeptidasas/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Acetamidas/síntesis química , Animales , Humanos , Concentración 50 Inhibidora , Lactamas/química , Lactamas/farmacología , Inhibidores de la Metaloproteinasa de la Matriz , Modelos Moleculares , Relación Estructura-Actividad , Porcinos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Asunto(s)
Benzodiazepinonas/síntesis química , Inhibidores Enzimáticos/síntesis química , Ácidos Hidroxámicos/síntesis química , Metaloendopeptidasas/antagonistas & inhibidores , Tiazepinas/síntesis química , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Proteínas ADAM , Proteína ADAM17 , Animales , Benzodiazepinonas/química , Benzodiazepinonas/farmacología , Proteínas Sanguíneas/metabolismo , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Humanos , Ácidos Hidroxámicos/química , Ácidos Hidroxámicos/farmacología , Leucocitos Mononucleares/efectos de los fármacos , Inhibidores de la Metaloproteinasa de la Matriz , Modelos Moleculares , Unión Proteica , Relación Estructura-Actividad , Porcinos , Tiazepinas/química , Tiazepinas/farmacología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
The discovery of novel 5,7-disubstituted[1,6]naphthyridines as potent inhibitors of Spleen Tyrosine Kinase (SYK) is discussed. The SAR reveals the necessity for a 7-aryl group with preference towards para substitution and that this in combination with 5-aminoalkylamino substituents further improved the potency of the compounds. The initial SAR as well as a survey of the other positions is discussed in detail.
Asunto(s)
Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Precursores Enzimáticos/antagonistas & inhibidores , Naftiridinas/química , Naftiridinas/farmacología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Bazo/enzimología , Animales , Humanos , Concentración 50 Inhibidora , Péptidos y Proteínas de Señalización Intracelular , Relación Estructura-Actividad , Quinasa SykRESUMEN
New gamma-lactam TACE inhibitors were designed from known MMP inhibitors. A homology model of TACE was built and examined to identify the S1' site as the key area for TACE selectivity over MMPs. Rational exploration of the P1'-S1' interactions resulted in the discovery of the 3,5-disubstituted benzyl ether as a TACE-selective P1' group. Further optimization led to the discovery of IK682 as a selective and orally bioavailable TACE inhibitor.