RESUMEN
The recent approval of aducanumab for Alzheimer's disease has heightened the interest in therapies targeting the amyloid hypothesis. Our research has focused on identification of novel compounds to improve amyloid processing by modulating gamma secretase activity, thereby addressing a significant biological deficit known to plague the familial form of the disease. Herein, we describe the design, synthesis, and optimization of new gamma secretase modulators (GSMs) based on previously reported oxadiazine 1. Potency improvements with a focus on predicted and measured properties afforded high-quality compounds further differentiated via robust Aß42 reductions in both rodents and nonhuman primates. Extensive preclinical profiling, efficacy studies, and safety studies resulted in the nomination of FRM-024, (+)-cis-5-(4-chlorophenyl)-6-cyclopropyl-3-(6-methoxy-5-(4-methyl-1H-imidazole-1-yl)pyridin-2-yl)-5,6-dihydro-4H-1,2,4-oxadiazine, as a GSM preclinical candidate for familial Alzheimer's disease.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Encéfalo/metabolismo , Descubrimiento de Drogas , Inhibidores y Moduladores de Gamma Secretasa/farmacología , Péptidos beta-Amiloides/metabolismo , Animales , Área Bajo la Curva , Perros , Inhibidores y Moduladores de Gamma Secretasa/farmacocinética , Semivida , Haplorrinos , Humanos , Ratones , Fragmentos de Péptidos/metabolismo , RatasRESUMEN
Herein we describe the design, synthesis, and evaluation of a novel series of oxadiazine-based gamma secretase modulators obtained via isosteric amide replacement and critical consideration of conformational restriction. Oxadiazine lead 47 possesses good in vitro potency with excellent predicted CNS drug-like properties and desirable ADME/PK profile. This lead compound demonstrated robust Aß42 reductions and subsequent Aß37 increases in both rodent brain and CSF at 30 mg/kg dosed orally.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Diseño de Fármacos , Oxazinas/química , Oxazinas/farmacología , Fragmentos de Péptidos/antagonistas & inhibidores , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Humanos , Macaca fascicularis , Ratones , Oxazinas/farmacocinética , Fragmentos de Péptidos/metabolismo , Ratas WistarRESUMEN
BACKGROUND: Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aß) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer's disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex. This analysis suggests that GSMs could potentially offset some of the effects of PS mutations on APP processing, thereby addressing the root cause of early onset FAD. Unfortunately, the field has generated few, if any, molecules with good central nervous system (CNS) drug-like properties to enable proof-of-mechanism studies. METHOD: We characterized the novel GSM FRM-36143 using multiple cellular assays to determine its in vitro potency and off-target activity as well as its potential to reverse the effect of PS mutations. We also tested its efficacy in vivo in wild-type mice and rats. RESULTS: FRM-36143 has much improved CNS drug-like properties compared to published GSMs. It has an in vitro EC50 for Aß42 of 35 nM in H4 cells, can reduce Aß42 to 58 % of the baseline in rat cerebrospinal fluid, and also increases the non-amyloidogenic peptides Aß37 and Aß38. It does not inhibit Notch processing, nor does it inhibit 24-dehydrocholesterol reductase (DHCR24) activity. Most interestingly, it can reverse the effects of presenilin mutations on APP processing in vitro. CONCLUSIONS: FRM-36143 possesses all the characteristics of a GSM in terms of Aß modulation Because FRM-36143 was able to reverse the effect of PS mutations, we suggest that targeting patients with this genetic defect would be the best approach at testing the efficacy of a GSM in the clinic. While the amyloid hypothesis is still being tested with ß-site APP-cleaving enzyme inhibitors and monoclonal antibodies in sporadic AD, we believe it is not a hypothesis for FAD. Since GSMs can correct the molecular defect caused by PS mutations, they have the promise to provide benefits to the patients when treated early enough in the course of the disease.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Nootrópicos/uso terapéutico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular Tumoral , Evaluación Preclínica de Medicamentos , Células HEK293 , Células HeLa , Compuestos Heterocíclicos de 4 o más Anillos/farmacocinética , Compuestos Heterocíclicos de 4 o más Anillos/toxicidad , Humanos , Masculino , Ratones , Ratones de la Cepa 129 , Mutación , Neocórtex/efectos de los fármacos , Neocórtex/metabolismo , Nootrópicos/farmacocinética , Nootrópicos/toxicidad , Presenilina-1/genética , Presenilina-1/metabolismo , Ratas WistarRESUMEN
The rapidly aging population desperately requires new therapies for Alzheimer's disease. Despite years of pharmaceutical research, limited clinical success has been realized, with several failed disease modification therapies in recent years. On the basis of compelling genetic evidence, the pharmaceutical industry has put a large emphasis on brain beta amyloid (Aß) either through its removal via antibodies or by targeting the proteases responsible for its production. In this Perspective, we focus on the development of small molecules that improve the activity of one such protease, gamma secretase, through an allosteric binding site to preferentially increase the concentration of the shorter non-amyloidogenic Aß species. After a few early failures due to poor drug-like properties, the industry is now on the cusp of delivering gamma secretase modulators for clinical proof-of-mechanism studies that combine potency and efficacy with improved drug-like properties such as lower cLogP, high central nervous system multiparameter optimization scores, and high sp(3) character.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Bibliotecas de Moléculas Pequeñas/farmacología , Enfermedad de Alzheimer/metabolismo , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/biosíntesis , Animales , Inhibidores Enzimáticos/química , Humanos , Bibliotecas de Moléculas Pequeñas/químicaRESUMEN
Mps1, also known as TTK, is a mitotic checkpoint protein kinase that has become a promising new target of cancer research. In an effort to improve the lead-likeness of our recent Mps1 purine lead compounds, a scaffold hopping exercise has been undertaken. Structure-based design, principles of conformational restriction, and subsequent scaffold hopping has led to novel pyrrolopyrimidine and quinazoline Mps1 inhibitors. These new single-digit nanomolar leads provide the basis for developing potent, novel Mps1 inhibitors with improved drug-like properties.
Asunto(s)
Proteínas de Ciclo Celular/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Purinas/química , Pirimidinas/química , Pirimidinas/farmacología , Pirroles/química , Pirroles/farmacología , Quinazolinas/química , Proteínas de Ciclo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Células HCT116 , Humanos , Modelos Moleculares , Unión Proteica , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Purinas/metabolismo , Purinas/farmacología , Pirimidinas/metabolismo , Pirroles/metabolismo , Quinazolinas/metabolismo , Quinazolinas/farmacología , Relación Estructura-ActividadRESUMEN
Efforts to optimize biological activity, novelty, selectivity and oral bioavailability of Mps1 inhibitors, from a purine based lead MPI-0479605, are described in this Letter. Mps1 biochemical activity and cytotoxicity in HCT-116 cell line were improved. On-target activity confirmation via mechanism based G2/M escape assay was demonstrated. Physico-chemical and ADME properties were optimized to improve oral bioavailability in mouse.
Asunto(s)
Adenina/análogos & derivados , Morfolinas/química , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Purinas/química , Adenina/química , Adenina/farmacocinética , Adenina/toxicidad , Administración Oral , Animales , Apoptosis/efectos de los fármacos , Sitios de Unión , Cristalografía por Rayos X , Puntos de Control de la Fase G2 del Ciclo Celular/efectos de los fármacos , Células HCT116 , Humanos , Puntos de Control de la Fase M del Ciclo Celular/efectos de los fármacos , Ratones , Conformación Molecular , Morfolinas/farmacocinética , Morfolinas/toxicidad , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/toxicidad , Proteínas Serina-Treonina Quinasas/metabolismo , Relación Estructura-ActividadRESUMEN
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC(50): 926 nM), potent mGluR5 NAMs showing excellent potencies (IC(50)s<50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (K(i): 21 nM) and antagonism (IC(50): 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk).
Asunto(s)
Benzamidas/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulación Alostérica , Animales , Trastornos de Ansiedad/tratamiento farmacológico , Benzamidas/farmacocinética , Benzamidas/uso terapéutico , Modelos Animales de Enfermedad , Ensayos Analíticos de Alto Rendimiento , Ratones , Piridinas/farmacocinética , Piridinas/uso terapéutico , Ratas , Receptor del Glutamato Metabotropico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMEN
Acidic mammalian chitinase (AMCase) is a member of the glycosyl hydrolase 18 family (EC 3.2.1.14) that has been implicated in the pathophysiology of allergic airway disease such as asthma. Small molecule inhibitors of AMCase were identified using a combination of high-throughput screening, fragment screening, and virtual screening techniques and characterized by enzyme inhibition and NMR and Biacore binding experiments. X-ray structures of the inhibitors in complex with AMCase revealed that the larger more potent HTS hits, e.g. 5-(4-(2-(4-bromophenoxy)ethyl)piperazine-1-yl)-1H-1,2,4-triazol-3-amine 1, spanned from the active site pocket to a hydrophobic pocket. Smaller fragments identified by FBS occupy both these pockets independently and suggest potential strategies for linking fragments. Compound 1 is a 200 nM AMCase inhibitor which reduced AMCase enzymatic activity in the bronchoalveolar lavage fluid in allergen-challenged mice after oral dosing.
Asunto(s)
Quitinasas/antagonistas & inhibidores , Modelos Moleculares , Piperazinas/síntesis química , Triazoles/síntesis química , Alérgenos/inmunología , Animales , Líquido del Lavado Bronquioalveolar , Dominio Catalítico , Cristalografía por Rayos X , Femenino , Interacciones Hidrofóbicas e Hidrofílicas , Espectroscopía de Resonancia Magnética , Ratones , Ratones Endogámicos C57BL , Piperazinas/química , Piperazinas/farmacología , Unión Proteica , Hipersensibilidad Respiratoria/tratamiento farmacológico , Hipersensibilidad Respiratoria/enzimología , Hipersensibilidad Respiratoria/inmunología , Relación Estructura-Actividad , Resonancia por Plasmón de Superficie , Triazoles/química , Triazoles/farmacologíaRESUMEN
We discovered 2-(4-substituted-pyrrolo[2,3-b]pyridin-3-yl)methylene-4-hydroxybenzofuran-3(2H)-ones as potent and selective ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Since phenolic OH groups pose metabolic liability, one of the two hydroxyl groups was selectively removed. The SAR data showed the structural features necessary for subnanomolar inhibitory activity against mTOR kinase as well as selectivity over PI3Kalpha. An X-ray co-crystal structure of one inhibitor with the mTOR-related PI3Kgamma revealed the key hydrogen bonding interactions.
Asunto(s)
Benzofuranos/química , Benzofuranos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Cristalografía por Rayos X , Humanos , Concentración 50 Inhibidora , Ratones , Ratones Desnudos , Microsomas/metabolismo , Modelos Moleculares , Neoplasias/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas/química , Fosfatidilinositol 3-Quinasas/metabolismo , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
A series of benzofuran-3-one indole phosphatidylinositol-3-kinases (PI3K) inhibitors identified via HTS has been prepared. The optimized inhibitors possess single digit nanomolar activity against p110alpha (PI3K-alpha), good pharmaceutical properties, selectivity versus p110gamma (PI3K-gamma), and tunable selectivity versus the mammalian target of rapamycin (mTOR). Modeling of compounds 9 and 32 in homology models of PI3K-alpha and mTOR supports the proposed rationale for selectivity. Compounds show activity in multiple cellular proliferation assays with signaling through the PI3K pathway confirmed via phospho-Akt inhibition in PC-3 cells.
Asunto(s)
Benzofuranos/farmacología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Benzofuranos/química , Línea Celular Tumoral , Humanos , Modelos Moleculares , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
Valosin-containing protein (VCP; also known as p97) is a member of the AAA ATPase family with a central role in the ubiquitin-degradation of misfolded proteins. VCP also exhibits antiapoptotic function and metastasis via activation of nuclear factor kappa-B signaling pathway. We have discovered that 2-anilino-4-aryl-1,3-thiazoles are potent drug-like inhibitors of this enzyme. The identified compounds show low nanomolar VCP potency, demonstrate SAR trends, and show activity in a mechanism based cellular assay. This series of compounds represents the first steps towards a novel, small molecule VCP inhibitor as a cancer therapeutic.
Asunto(s)
Adenosina Trifosfatasas/antagonistas & inhibidores , Compuestos de Anilina/química , Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inhibidores , Tiazoles/química , Adenosina Trifosfatasas/metabolismo , Compuestos de Anilina/síntesis química , Antineoplásicos/síntesis química , Antineoplásicos/farmacología , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , FN-kappa B/metabolismo , Transducción de Señal , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacología , Proteína que Contiene ValosinaRESUMEN
Series of purine and pyrazolo[3,4-d]pyrimidine inhibitors of phosphatidylinositol-3-kinases (PI3K) have been prepared. The optimized purine inhibitors show good potency in a PI3K p110alpha (PI3K-alpha) fluorescence polarization assay with good selectivity versus PI3K p110gamma (PI3K-gamma) and the mammalian target of rapamycin (mTOR). The related pyrazolo[3,4-d]pyrimidines show potent PI3K-alpha and mTOR inhibition with good selectivity versus PI3K-gamma. Representative compounds showed activity in a cellular proliferation assay against Caco-2 colorectal, LoVo colorectal and PC3MM2 prostate adenocarcinoma cancer cells. Signaling through the PI3K pathway was confirmed via inhibition of phospho-AKT in MDA-361 cells.
Asunto(s)
Inhibidores de las Quinasa Fosfoinosítidos-3 , Purinas/química , Pirazoles/química , Piridinas/química , Sitios de Unión , Células CACO-2 , Línea Celular Tumoral , Cristalografía por Rayos X , Inmunoensayo de Polarización Fluorescente , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Purinas/síntesis química , Purinas/farmacología , Pirazoles/síntesis química , Pirazoles/farmacología , Piridinas/síntesis química , Piridinas/farmacología , Relación Estructura-Actividad , Serina-Treonina Quinasas TORRESUMEN
A series of (hetero)arylpyrimidines agonists of the Wnt-beta-catenin cellular messaging system have been prepared. These compounds show activity in U2OS cells transfected with Wnt-3a, TCF-luciferase, Dkk-1 and tk-Renilla. Selected compounds show minimal GSK-3beta inhibition indicating that the Wnt-beta-catenin agonism activity most likely comes from interaction at Wnt-3a/Dkk-1. Two examples 1 and 25 show in vivo osteogenic activity in a mouse calvaria model. One example 1 is shown to activate non-phosphorylated beta-catenin formation in bone.
Asunto(s)
Imidazoles/química , Pirimidinas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Desarrollo Óseo/efectos de los fármacos , Línea Celular Tumoral , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3 beta , Humanos , Imidazoles/síntesis química , Imidazoles/farmacología , Péptidos y Proteínas de Señalización Intercelular/genética , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Ratones , Ratones Endogámicos C57BL , Pirimidinas/síntesis química , Pirimidinas/farmacología , Proteínas Recombinantes de Fusión/agonistas , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Cráneo/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/agonistasRESUMEN
This article describes the syntheses and SAR of a series of imidazolopyrimidine derivatives, which are evaluated as inhibitors of PI3-Kinase (PI3K) and mTOR. These compounds were found to be ATP competitive with good tumor cell growth inhibition, and suppression of pathway specific biomakers such as phosphorylation of Akt at T308.
Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Inhibidores de las Quinasa Fosfoinosítidos-3 , Inhibidores de Proteínas Quinasas/química , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Pirimidinas/química , Adenosina Trifosfato/química , Adenosina Trifosfato/metabolismo , Sitios de Unión , Unión Competitiva , Línea Celular Tumoral , Simulación por Computador , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirimidinas/síntesis química , Pirimidinas/farmacología , Serina-Treonina Quinasas TORRESUMEN
The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, metabolism, and angiogenesis and an emerging target in cancer research. High throughput screening (HTS) of our compound collection led to the identification of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model based on an X-ray crystal structure of closely related PI3Kgamma led to the discovery of 6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors with potential for development for cancer therapy.
Asunto(s)
Descubrimiento de Drogas , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Quinasas/metabolismo , Pirimidinas/farmacología , Unión Competitiva , Línea Celular Tumoral , Humanos , Concentración 50 Inhibidora , Modelos Moleculares , Conformación Molecular , Peso Molecular , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/metabolismo , Proteínas Quinasas/química , Pirimidinas/síntesis química , Pirimidinas/química , Pirimidinas/metabolismo , Transducción de Señal/efectos de los fármacos , Especificidad por Sustrato , Serina-Treonina Quinasas TORRESUMEN
N-((8-Hydroxy-5-substituted-quinolin-7-yl)(phenyl)methyl)-2-phenyloxy/amino-acetamide inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared. Selected compounds 10, 14, 25, and 53 show sub-microM ADAMTS-5 potency and good selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP-13, and MMP-12. Compound 53 shows a good balance of potent ADAMTS-5 inhibition, moderate CYP3A4 inhibition and good rat liver microsome stability. This series of compounds represents progress towards selective ADAMTS-5 inhibitors as disease modifying osteoarthritis agents.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Proteínas ADAM/química , Acetamidas/síntesis química , Acetamidas/farmacología , Proteínas ADAM/metabolismo , Proteína ADAMTS4 , Proteína ADAMTS5 , Animales , Química Farmacéutica/métodos , Citocromo P-450 CYP3A , Inhibidores del Citocromo P-450 CYP3A , Inhibidores Enzimáticos del Citocromo P-450 , Diseño de Fármacos , Humanos , Concentración 50 Inhibidora , Microsomas Hepáticos/efectos de los fármacos , Modelos Químicos , Osteoartritis/tratamiento farmacológico , Procolágeno N-Endopeptidasa/metabolismo , RatasRESUMEN
5'-Phenyl-3'H-spiro[indoline-3,2'-[1,3,4]thiadiazol]-2-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. Selected compounds 23, 33-35 show sub-micromolar ADAMTS-5 potency and strong SAR trends with selectivity over the related metalloproteases ADAMTS-4 (Aggrecanase-1), MMP12, and MMP13. This series of compounds represents progress toward a selective ADAMTS-5 inhibitor as a disease modifying osteoarthritis drug.
Asunto(s)
Endopeptidasas/metabolismo , Indoles/química , Inhibidores de Proteasas/química , Inhibidores de Proteasas/farmacología , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Tiadiazoles/química , Estructura Molecular , Inhibidores de Proteasas/síntesis química , Compuestos de Espiro/síntesis química , Relación Estructura-Actividad , Tiadiazoles/síntesis química , Tiadiazoles/farmacologíaRESUMEN
5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug.
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Tiazolidinedionas/síntesis química , Tiazolidinedionas/farmacología , Proteína ADAMTS5 , Quelantes , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Humanos , Metaloproteasas/antagonistas & inhibidores , Osteoartritis/tratamiento farmacológico , Relación Estructura-Actividad , ZincRESUMEN
A series of 5-((1H-pyrazol-4-yl)methylene)-2-thioxothiazolidin-4-one inhibitors of ADAMTS-5 (aggrecanase-2) is described. These compounds show microM functional inhibition of ADAMTS-5, and represent a new class of agents with the potential of inhibiting degradation of aggrecan, a major component of cartilage which is lost in osteoporosis. Compound 12 is noteworthy in that it has an ADAMTS-5 IC50: 1.1 microM and shows >40-fold functional selectivity over ADAMTS-4 (aggrecanase-1).
Asunto(s)
Proteínas ADAM/antagonistas & inhibidores , Tiazolidinedionas/síntesis química , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanos/efectos de los fármacos , Agrecanos/metabolismo , Cartílago , Humanos , Concentración 50 Inhibidora , Osteoporosis/tratamiento farmacológico , Procolágeno N-Endopeptidasa , Relación Estructura-Actividad , Tiazolidinedionas/farmacologíaRESUMEN
[reaction: see text] An expedient synthesis of diverse 2-amino-4-heteroarylpyrimidines via a 2-chloropyrimidine intermediate is described. A series of potentially biologically active analogues have been synthesized in two parallel steps to afford focused arrays.