RESUMO
C5a is a terminal product of the complement cascade that activates and attracts inflammatory cells including granulocytes, mast cells and macrophages via a specific GPCR, the C5a receptor (C5aR). Inhibition of C5a/C5aR interaction has been shown to be efficacious in several animal models of autoimmune diseases, including RA, SLE and asthma. This account reports the discovery of a new class of C5aR antagonists through high-throughput screening. The lead compounds in this series are selective and block C5a binding, C5a-promoted calcium flux in human neutrophils with nanomolar potency.
Assuntos
Receptor da Anafilatoxina C5a/antagonistas & inibidores , Sulfonamidas/química , Animais , Linhagem Celular , Ensaios de Triagem em Larga Escala , Humanos , Camundongos , Conformação Molecular , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ligação Proteica , Receptor da Anafilatoxina C5a/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/farmacologiaRESUMO
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Assuntos
Benzamidas/química , Benzimidazóis/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3 , Animais , Benzamidas/sangue , Benzamidas/metabolismo , Benzimidazóis/sangue , Benzimidazóis/metabolismo , Células CACO-2 , Linhagem Celular , Antagonistas dos Receptores Histamínicos H3/sangue , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Indóis/sangue , Indóis/química , Indóis/metabolismo , Ligação Proteica , Pirrolidinas/sangue , Pirrolidinas/metabolismo , Ratos , Receptores Histamínicos H3/sangue , Receptores Histamínicos H3/metabolismoRESUMO
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
8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidantoínas/química , Imidazóis/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Hidantoínas/síntese química , Hidantoínas/farmacologia , Ligação de Hidrogênio , Imidazóis/síntese química , Imidazóis/farmacologiaRESUMO
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Isoleucina/análogos & derivados , Receptor Notch1/metabolismo , Álcoois , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Desenho de Fármacos , Humanos , Isoleucina/química , Modelos Químicos , Propanolaminas/química , Sulfonamidas/químicaRESUMO
A novel series of non-hydroxamate tryptophan sulfonamide derivatives containing a butynyloxy P1' moiety was identified as inhibitors of TNF-alpha converting enzyme (TACE). The structure-activity relationship of the series was examined via substitution on the tryptophan indole ring. Of the compounds investigated, 2-(4-(but-2-ynyloxy)phenylsulfonamido)-3-(1-(4-methoxybenzyl)-1H-indol-3-yl)propanoic acid (12p) has the best in vitro potency against isolated TACE enzyme with an IC(50) of 80 nM. Compound 12p also shows good selectivity over MMP-1, -13, -14.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Sulfonamidas/química , Triptofano/análogos & derivados , Proteína ADAM17 , Animais , Ácidos Carboxílicos/química , Linhagem Celular , Ativação Enzimática/efeitos dos fármacos , Concentração Inibidora 50 , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/farmacologia , Triptofano/síntese química , Triptofano/química , Triptofano/farmacologiaRESUMO
The proteolytic enzyme beta-secretase (BACE-1) produces amyloid beta (Abeta) peptide, the primary constituent of neurofibrillary plaques, implicated in Alzheimer's disease, by cleavage of the amyloid precursor protein. A small molecule inhibitor of BACE-1, (diaminomethylene)-2,5-diphenyl-1H-pyrrole-1-acetamide (1, BACE-1 IC(50)=3.7 microM), was recently described, representing a new small molecule lead. Initial SAR investigation demonstrated the potential of accessing the nearby S(3) and S(1)(') substrate binding pockets of the BACE-1 enzyme by building substituents off one of the phenyl substituents and guanidinyl functional group. We report here the optimization of guanidinyl functional group substituents on 1, leading to potent submicromolar BACE-1 inhibitors.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Guanidina/farmacologia , Pirróis/química , Doença de Alzheimer/enzimologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Inibidores Enzimáticos/química , Guanidina/química , HumanosRESUMO
Proteolytic cleavage of amyloid precursor protein by beta-secretase (BACE-1) and gamma-secretase leads to formation of beta-amyloid (A beta) a key component of amyloid plaques, which are considered the hallmark of Alzheimer's disease. Small molecule inhibitors of BACE-1 may reduce levels of A beta and thus have therapeutic potential for treating Alzheimer's disease. We recently reported the identification of a novel small molecule BACE-1 inhibitor N-[2-(2,5-diphenyl-pyrrol-1-yl)-acetyl]guanidine (3.a.1). We report here the initial hit-to-lead optimization of this hit and the SAR around the aryl groups occupying the S(1) and S(2') pockets leading to submicromolar BACE-1 inhibitors.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Técnicas de Química Combinatória , Guanidinas/síntese química , Guanidinas/farmacologia , Pirróis/química , Cristalografia por Raios X , Guanidinas/química , Conformação Molecular , Estrutura Molecular , Pirróis/farmacologia , Relação Estrutura-AtividadeRESUMO
N1-Arylsulfonyltryptamines have been identified as 5-HT6 receptor ligands. In particular, N1-(6-chloroimidazo[2,1-b][1,3]thiazole-5-sulfonyl)tryptamine (11q) is a high affinity, potent full agonist (5-HT6 Ki = 2 nM, EC50 = 6.5 nM, Emax = 95.5%). Compound 11q is selective in a panel of over 40 receptors and ion channels, has good pharmacokinetic profile, has been shown to increase GABA levels in the rat frontal cortex, and is active in the schedule-induced polydipsia model for obsessive compulsive disorders.
Assuntos
Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/síntese química , Tiazóis/química , Triptaminas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Cães , Lobo Frontal/metabolismo , Haplorrinos , Humanos , Técnicas In Vitro , Camundongos , Microdiálise , Microssomos Hepáticos/metabolismo , Ensaio Radioligante , Ratos , Agonistas do Receptor de Serotonina/farmacocinética , Agonistas do Receptor de Serotonina/farmacologia , Solubilidade , Relação Estrutura-Atividade , Tiazóis/farmacocinética , Tiazóis/farmacologia , Triptaminas/química , Triptaminas/farmacocinética , Triptaminas/farmacologia , Ácido gama-Aminobutírico/metabolismoRESUMO
Through high throughput screening, substituted proline sulfonamide 6 was identified as HCV NS5b RNA-dependent RNA polymerase inhibitor. Optimization of various regions of the lead molecule resulted in compounds that displayed good potency and selectivity. The crystal structure of 6 and NS5b polymerase complex confirmed the binding near the active site region. The optimization approach and SAR are discussed in detail.
Assuntos
Antivirais/síntese química , Prolina/análogos & derivados , Prolina/síntese química , Sulfonamidas/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/química , Antivirais/química , Sítios de Ligação , Cristalografia por Raios X , Modelos Moleculares , Conformação Molecular , Prolina/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
Assuntos
Secretases da Proteína Precursora do Amiloide/química , Guanidinas/síntese química , Peptídeos/química , Inibidores de Proteases/síntese química , Domínio Catalítico , Cristalografia por Raios X , Guanidinas/química , Ligação de Hidrogênio , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Inibidores de Proteases/química , Relação Estrutura-AtividadeRESUMO
5-Arylsulfonylamido-3-(pyrrolidin-2-ylmethyl)-1H-indoles have been identified as high-affinity 5-HT(6) receptor ligands. Within this class, several of the (R)-enantiomers were potent agonists having EC(50) values of 1 nM or less and functioning as full agonists while the (S)-enantiomers displayed moderate antagonist activity.
Assuntos
Indóis/síntese química , Pirrolidinas/síntese química , Receptores de Serotonina/efeitos dos fármacos , Sulfonamidas/síntese química , AMP Cíclico/agonistas , AMP Cíclico/antagonistas & inibidores , AMP Cíclico/biossíntese , Células HeLa , Humanos , Indóis/química , Indóis/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
A series of pyrazolo[4,3-d]pyrimidine sulfonamides and pyrazolo[3,4-d]pyrimidine sulfonamides have been synthesized. These compounds increase transcription of a calcitonin-luciferase promoter and production of cellular calcitonin in a calcitonin-secretion/RIA assay with minimized phosphodiesterase type 4 inhibitory activity at 30 microM as compared to structurally related xanthine methylene ketones such as denbufyllene. These two series are notable examples of small molecules that act as CT-inducers, a method to potentially treat bone loss diseases.
Assuntos
Calcitonina/biossíntese , Pirimidinas/síntese química , Sulfonamidas/síntese química , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Calcitonina/genética , Linhagem Celular , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Inibidores de Fosfodiesterase/síntese química , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Radioimunoensaio , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Ativação Transcricional , Xantinas/química , Xantinas/farmacologiaRESUMO
Through high throughput screening of various libraries, substituted styryl naphthalene 6 was identified as an HCMV protease inhibitor. Optimization of various regions of the lead molecule using parallel synthesis resulted in 1,6-substituted naphthalenes 19d-i. These compounds displayed good potency and were selective over elastase, trypsin, and chymotrypsin. The optimization approach on lead compound 6 in three different regions of the molecule using parallel solution-phase synthesis and the corresponding SAR are discussed in detail.
Assuntos
2-Naftilamina/síntese química , Citomegalovirus/química , Naftalenos/síntese química , Inibidores de Proteases/síntese química , Serina Endopeptidases/química , Sulfonamidas/síntese química , 2-Naftilamina/análogos & derivados , 2-Naftilamina/química , Bases de Dados Factuais , Naftalenos/química , Inibidores de Proteases/química , Relação Estrutura-Atividade , Sulfonamidas/químicaRESUMO
A novel series of HCV NS5B RNA-dependent RNA polymerase inhibitors containing a pyrano[3,4-b]indole scaffold is described leading to the discovery of compound 16, a highly potent and selective inhibitor that is active in the replicon system.
Assuntos
Antivirais/síntese química , RNA Polimerases Dirigidas por DNA/antagonistas & inibidores , Hepacivirus/enzimologia , Indóis/síntese química , Piranos/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Cristalografia por Raios X , RNA Polimerases Dirigidas por DNA/química , Indóis/química , Piranos/química , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/químicaRESUMO
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
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
The protein kinase C (PKC) family of serine/threonine kinases is implicated in a wide variety of cellular processes. The PKC theta (PKCtheta) isoform is involved in TCR signal transduction and T cell activation and regulates T cell mediated diseases, including lung inflammation and airway hyperresponsiveness. Thus inhibition of PKCtheta enzyme activity by a small molecule represents an attractive strategy for the treatment of asthma. A PKCtheta high-throughput screening (HTS) campaign led to the identification of 4-(3-bromophenylamino)-5-(3,4-dimethoxyphenyl)-3-pyridinecarbonitrile 4a, a low microM ATP competitive PKCtheta inhibitor. Structure based hit-to-lead optimization led to the identification of 5-(3,4-dimethoxyphenyl)-4-(1H-indol-5-ylamino)-3-pyridinecarbonitrile 4p, a 70 nM PKCtheta inhibitor. Compound 4p was selective for inhibition of novel PKC isoforms over a panel of 21 serine/threonine, tyrosine, and phosphoinositol kinases, in addition to the conventional and atypical PKCs, PKCbeta, and PKCzeta, respectively. Compound 4p also inhibited IL-2 production in antiCD3/anti-CD28 activated T cells enriched from splenocytes.
Assuntos
Indóis/farmacologia , Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Feminino , Indóis/síntese química , Indóis/química , Interleucina-2/antagonistas & inibidores , Interleucina-2/biossíntese , Isoenzimas/deficiência , Isoenzimas/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Moleculares , Estrutura Molecular , Nitrilas/síntese química , Nitrilas/química , Proteína Quinase C/deficiência , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Piridinas/síntese química , Piridinas/química , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Estereoisomerismo , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologiaRESUMO
A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 3,4-dihydro-1H-[1]-benzothieno[2,3-c]pyran and 3,4-dihydro-1H-pyrano[3,4-b]benzofuran scaffolds were designed and synthesized. Optimization of the alkyl substituent in the pyran ring showed preference for an n-propyl group, while 5,8-disubstitution pattern is preferred for the aromatic region. Analog 19 displayed potent activity with an IC(50) of 50 nM against HCV NS5B enzyme and was selective over a panel of polymerases.
Assuntos
Benzofuranos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Piranos , RNA Polimerase Dependente de RNA/antagonistas & inibidores , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Linhagem Celular Tumoral , Chlorocebus aethiops , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piranos/síntese química , Piranos/química , Piranos/farmacologia , RNA Polimerase Dependente de RNA/química , Relação Estrutura-Atividade , Células Vero , Proteínas não Estruturais Virais/químicaRESUMO
A novel class of HCV NS5B RNA dependent RNA polymerase inhibitors containing 2,3,4,9-tetrahydro-1H-carbazole and 1,2,3,4-tetrahydro-cyclopenta[b]indole scaffolds were designed and synthesized. Optimization of the aromatic region showed preference for 5,8-disubstitution pattern in both the scaffolds examined while favoring the n-propyl moiety for the C-1 position. 1,2,3,4-tetrahydro-cyclopenta[b]indole scaffold was slightly more potent than the corresponding 2,3,4,9-tetrahydro-1H-carbazole and analogue 36 displayed an IC50 of 550 nM against HCV NS5B enzyme.