RESUMO
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.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Encéfalo/metabolismo , Descoberta de Drogas , Inibidores e Moduladores de Secretases gama/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Área Sob a Curva , Cães , Inibidores e Moduladores de Secretases gama/farmacocinética , Meia-Vida , Haplorrinos , Humanos , Camundongos , Fragmentos de Peptídeos/metabolismo , RatosRESUMO
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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Desenho de Fármacos , Oxazinas/química , Oxazinas/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Humanos , Macaca fascicularis , Camundongos , Oxazinas/farmacocinética , Fragmentos de Peptídeos/metabolismo , Ratos WistarRESUMO
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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Nootrópicos/uso terapêutico , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular Tumoral , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Células HeLa , Compostos Heterocíclicos de 4 ou mais Anéis/farmacocinética , Compostos Heterocíclicos de 4 ou mais Anéis/toxicidade , Humanos , Masculino , Camundongos , Camundongos da Linhagem 129 , Mutação , Neocórtex/efeitos dos fármacos , Neocórtex/metabolismo , Nootrópicos/farmacocinética , Nootrópicos/toxicidade , Presenilina-1/genética , Presenilina-1/metabolismo , Ratos WistarRESUMO
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.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/biossíntese , Animais , Inibidores Enzimáticos/química , Humanos , Bibliotecas de Moléculas Pequenas/químicaRESUMO
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.
Assuntos
Proteínas de Ciclo Celular/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Purinas/química , Pirimidinas/química , Pirimidinas/farmacologia , Pirróis/química , Pirróis/farmacologia , Quinazolinas/química , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Células HCT116 , Humanos , Modelos Moleculares , Ligação Proteica , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/metabolismo , Purinas/metabolismo , Purinas/farmacologia , Pirimidinas/metabolismo , Pirróis/metabolismo , Quinazolinas/metabolismo , Quinazolinas/farmacologia , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Adenina/análogos & derivados , Morfolinas/química , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Purinas/química , Adenina/química , Adenina/farmacocinética , Adenina/toxicidade , Administração Oral , Animais , Apoptose/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Células HCT116 , Humanos , Pontos de Checagem da Fase M do Ciclo Celular/efeitos dos fármacos , Camundongos , Conformação Molecular , Morfolinas/farmacocinética , Morfolinas/toxicidade , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/toxicidade , Proteínas Serina-Treonina Quinases/metabolismo , Relação Estrutura-AtividadeRESUMO
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).
Assuntos
Benzamidas/química , Piridinas/química , Receptores de Glutamato Metabotrópico/química , Regulação Alostérica , Animais , Transtornos de Ansiedade/tratamento farmacológico , Benzamidas/farmacocinética , Benzamidas/uso terapêutico , Modelos Animais de Doenças , Ensaios de Triagem em Larga Escala , Camundongos , Piridinas/farmacocinética , Piridinas/uso terapêutico , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismoRESUMO
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.
Assuntos
Quitinases/antagonistas & inibidores , Modelos Moleculares , Piperazinas/síntese química , Triazóis/síntese química , Alérgenos/imunologia , Animais , Líquido da Lavagem Broncoalveolar , Domínio Catalítico , Cristalografia por Raios X , Feminino , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos C57BL , Piperazinas/química , Piperazinas/farmacologia , Ligação Proteica , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/enzimologia , Hipersensibilidade Respiratória/imunologia , Relação Estrutura-Atividade , Ressonância de Plasmônio de Superfície , Triazóis/química , Triazóis/farmacologiaRESUMO
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.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Cristalografia por Raios X , Humanos , Concentração Inibidora 50 , Camundongos , Camundongos Nus , Microssomos/metabolismo , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
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.
Assuntos
Benzofuranos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Benzofuranos/química , Linhagem Celular Tumoral , Humanos , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
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.
Assuntos
Adenosina Trifosfatases/antagonistas & inibidores , Compostos de Anilina/química , Antineoplásicos/química , Proteínas de Ciclo Celular/antagonistas & inibidores , Tiazóis/química , Adenosina Trifosfatases/metabolismo , Compostos de Anilina/síntese química , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/metabolismo , Células HeLa , Humanos , NF-kappa B/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacologia , Proteína com ValosinaRESUMO
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.
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Purinas/química , Pirazóis/química , Piridinas/química , Sítios de Ligação , Células CACO-2 , Linhagem Celular Tumoral , Cristalografia por Raios X , Imunoensaio de Fluorescência por Polarização , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Purinas/síntese química , Purinas/farmacologia , Pirazóis/síntese química , Pirazóis/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TORRESUMO
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.
Assuntos
Imidazóis/química , Pirimidinas/química , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animais , Desenvolvimento Ósseo/efeitos dos fármacos , Linhagem Celular Tumoral , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proteínas Recombinantes de Fusão/agonistas , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Crânio/metabolismo , Proteínas Wnt/agonistas , Proteínas Wnt/genética , Proteína Wnt3 , Proteína Wnt3A , beta Catenina/agonistasRESUMO
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.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/química , Trifosfato de Adenosina/química , Trifosfato de Adenosina/metabolismo , Sítios de Ligação , Ligação Competitiva , Linhagem Celular Tumoral , Simulação por Computador , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pirimidinas/síntese química , Pirimidinas/farmacologia , Serina-Treonina Quinases TORRESUMO
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.
Assuntos
Descoberta de Drogas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Quinases/metabolismo , Pirimidinas/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Peso Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Proteínas Quinases/química , Pirimidinas/síntese química , Pirimidinas/química , Pirimidinas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Especificidade por Substrato , Serina-Treonina Quinases TORRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/química , Acetamidas/síntese química , Acetamidas/farmacologia , Proteínas ADAM/metabolismo , Proteína ADAMTS4 , Proteína ADAMTS5 , Animais , Química Farmacêutica/métodos , Citocromo P-450 CYP3A , Inibidores do Citocromo P-450 CYP3A , Inibidores das Enzimas do Citocromo P-450 , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Microssomos Hepáticos/efeitos dos fármacos , Modelos Químicos , Osteoartrite/tratamento farmacológico , Pró-Colágeno N-Endopeptidase/metabolismo , RatosRESUMO
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.
Assuntos
Endopeptidases/metabolismo , Indóis/química , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Tiadiazóis/química , Estrutura Molecular , Inibidores de Proteases/síntese química , Compostos de Espiro/síntese química , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacologiaRESUMO
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.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Tiazolidinedionas/síntese química , Tiazolidinedionas/farmacologia , Proteína ADAMTS5 , Quelantes , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Humanos , Metaloproteases/antagonistas & inibidores , Osteoartrite/tratamento farmacológico , Relação Estrutura-Atividade , ZincoRESUMO
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).
Assuntos
Proteínas ADAM/antagonistas & inibidores , Tiazolidinedionas/síntese química , Proteína ADAMTS4 , Proteína ADAMTS5 , Agrecanas/efeitos dos fármacos , Agrecanas/metabolismo , Cartilagem , Humanos , Concentração Inibidora 50 , Osteoporose/tratamento farmacológico , Pró-Colágeno N-Endopeptidase , Relação Estrutura-Atividade , Tiazolidinedionas/farmacologiaRESUMO
[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.