RESUMO
We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and â¼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for â¼8â¯h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Animais , Relação Dose-Resposta a Droga , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Camundongos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Herein we report the design and synthesis of a series of novel bicyclic DGAT1 inhibitors with a carboxylic acid moiety. The optimization of the initial lead compound 7 based on in vitro and in vivo activity led to the discovery of potent indoline and quinoline classes of DGAT1 inhibitors. The structure-activity relationship studies of these novel series of bicyclic carboxylic acid derivatives as DGAT1 inhibitors are described.
Assuntos
Ácidos Carboxílicos/farmacologia , Diacilglicerol O-Aciltransferase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Quinolonas/farmacologia , Animais , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Diacilglicerol O-Aciltransferase/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Camundongos , Modelos Moleculares , Estrutura Molecular , Quinolonas/síntese química , Quinolonas/química , Relação Estrutura-AtividadeRESUMO
Novel, low brain penetrant, orally bioavailable CB1 receptor agonists were designed starting from a mature lead series of potent brain penetrant CB1 receptor agonists. Increasing the calculated polar surface area was found to be a good strategy for reducing brain penetration whilst retaining drug-like properties. This in silico approach led to the discovery of LBP1, an orally bioavailable, low brain penetrant CB1 receptor agonist with robust activity in rodent models of neuropathic pain and a good preclinical therapeutic profile, which was selected for clinical development.
Assuntos
Desenho de Fármacos , Indóis/síntese química , Neuralgia/tratamento farmacológico , Oxidiazóis/síntese química , Receptor CB1 de Canabinoide/agonistas , Animais , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Células CACO-2 , Humanos , Indóis/química , Indóis/farmacocinética , Camundongos , Oxidiazóis/química , Oxidiazóis/farmacocinética , RatosRESUMO
The NLRP3 inflammasome is a multiprotein complex that facilitates activation and release of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 in response to infection or endogenous stimuli. It can be inappropriately activated by a range of danger signals resulting in chronic, low-grade inflammation underlying a multitude of diseases, such as Alzheimer's disease, Parkinson's disease, osteoarthritis, and gout. The discovery of potent and specific NLRP3 inhibitors could reduce the burden of several common morbidities. In this study, we identified a weakly potent triazolopyrimidone hit (1) following an in silico modeling exercise. This was optimized to furnish potent and selective small molecule NLRP3 inflammasome inhibitors. Compounds such as NDT-30805 could be useful tool molecules for a scaffold-hopping or pharmacophore generation project or used as leads toward the development of clinical candidates.
RESUMO
The pharmacokinetic based optimisation of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 24 was found to be a highly potent and selective cannabinoid CB(1) antagonist with high predicted human oral bioavailability.
Assuntos
Indóis/farmacocinética , Receptor CB1 de Canabinoide/antagonistas & inibidores , Administração Oral , Disponibilidade Biológica , Humanos , Indóis/administração & dosagem , Indóis/química , Relação Estrutura-AtividadeRESUMO
The discovery and structure-activity relationship of a novel series of indole-2-carboxamide antagonists of the cannabinoid CB(1) receptor is disclosed. Compound 26i was found to be a high potency, selective cannabinoid CB(1) antagonist.
Assuntos
Amidas/química , Indóis/química , Receptor CB1 de Canabinoide/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Cães , Avaliação Pré-Clínica de Medicamentos , Indóis/síntese química , Indóis/farmacocinética , Masculino , Camundongos , Modelos Moleculares , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
The previously described lead compound 5 is a potent and selective V(1A) antagonist with affinity at both the rat and human receptor, but displays poor oral bioavailability and moderate clearance. We report herein the successful optimisation of the pharmacokinetic (PK) properties to afford the potent, selective, orally bioavailable and CNS penetrant compound 15f. A custom optimisation approach was required which demonstrated the value of using early, rapid in vivo PK studies to show improvements in oral exposure. Such assays may be of particular value where low oral bioavailability is anticipated to be multifactorial (e.g., permeability, gut wall metabolism and/or transport) where satisfactory modelling of in vitro data is likely to be difficult within a drug discovery context.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Fenilalanina/análogos & derivados , Administração Oral , Animais , Disponibilidade Biológica , Humanos , Masculino , Peptídeos/química , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacocinética , Ligação Proteica , Ratos , Ratos Wistar , Receptores de Vasopressinas/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Novel 3-(1H-indol-3-yl)-1,2,4-oxadiazoles and -thiadiazoles were synthesized and found to be potent CB1 cannabinoid receptor agonists. The oral bioavailability of these compounds could be dramatically improved by optimization studies of the side chains attached to the indole and oxadiazole cores, leading to identification of a CB1 receptor agonist with good oral activity in a range of preclinical models of antinociception and antihyperalgesia.
Assuntos
Compostos Heterocíclicos/farmacocinética , Receptor CB1 de Canabinoide/agonistas , Administração Oral , Animais , Disponibilidade Biológica , Descoberta de Drogas , Compostos Heterocíclicos/administração & dosagem , RatosRESUMO
Novel indole-3-heterocycles were designed and synthesized and found to be potent CB1 receptor agonists. Starting from a microsomally unstable lead 1, a bioisostere approach replacing a piperazine amide was undertaken. This was found to be a good strategy for improving stability both in vitro and in vivo. This led to the discovery of 24, which had an increased duration of action in the mouse tail flick test in comparison to the lead 1.
Assuntos
Compostos Heterocíclicos/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Tiadiazóis/química , Animais , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Indóis/síntese química , Indóis/farmacocinética , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiadiazóis/síntese química , Tiadiazóis/farmacocinéticaRESUMO
The discovery of a novel series of 8-azabicyclo[3.2.1]octan-3-yl)-3-(4-chlorophenyl) propanamide antagonists of the vasopressin V(1A) receptor is disclosed. Compounds 47 and 48 were found to be high affinity, selective vasopressin V(1A) antagonists.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Antagonistas dos Receptores de Hormônios Antidiuréticos , Descoberta de Drogas , Amidas/química , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Células Cultivadas , Ciclização , Humanos , Fígado/metabolismo , Estrutura Molecular , Ligação Proteica/efeitos dos fármacosRESUMO
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development.
Assuntos
Compostos Heterocíclicos/química , Indóis/química , Receptor CB1 de Canabinoide/agonistas , Tiazóis/química , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Cães , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacocinética , Camundongos , Ratos , Ratos Wistar , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-Atividade , Tiazóis/síntese química , Tiazóis/farmacocinéticaRESUMO
Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Piridonas/química , Pirimidinonas/química , Animais , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Sítios de Ligação , Encéfalo/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Cristalografia por Raios X , Desenho de Fármacos , Meia-Vida , Humanos , Doença de Huntington/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Dinâmica Molecular , Morfolinos/química , Piridonas/metabolismo , Piridonas/uso terapêutico , Pirimidinonas/metabolismo , Pirimidinonas/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Bicyclic piperazine derivatives were synthesized as conformationally constrained analogs of N-alkyl piperazines and were found to be potent CB1 receptor agonists. The CB1 receptor agonist activity was dependent upon the absolute configuration of the chiral center of the bicyclic ring system. Although the conformational constraint did not protect the compounds from metabolism by N-dealkylation, several bicyclic analogs were found to be more potent than the unconstrained lead compound. Compound 8b demonstrated potent antinociceptive activity in vivo.
Assuntos
Amidas/química , Compostos Azabicíclicos/síntese química , Compostos Bicíclicos com Pontes/química , Indóis/síntese química , Piperazinas/química , Receptor CB1 de Canabinoide/agonistas , Animais , Compostos Azabicíclicos/química , Compostos Azabicíclicos/farmacologia , Desenho de Fármacos , Humanos , Indóis/química , Indóis/farmacologia , Camundongos , Microssomos Hepáticos/metabolismo , Piperazinas/síntese química , Piperazinas/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
Antagonists of the 5-HT(6) receptor have been shown to improve cognitive function in a wide range of animal models and as such may prove to be attractive agents for the symptomatic treatment of cognitive disorders such as Alzheimer's disease (AD) and schizophrenia. We report herein the identification and SAR around N-(2-aminoalkyl)-1-(arylsulfonyl)indoline-3-carboxamides-a novel chemotype of 5-HT(6) antagonists.
Assuntos
Amidas/química , Indóis/química , Receptores de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/síntese química , Amidas/farmacologia , Animais , Disponibilidade Biológica , Descoberta de Drogas , Humanos , Indóis/farmacologia , Masculino , Microssomos , Farmacocinética , Ratos , Ratos Wistar , Agonistas do Receptor de Serotonina/química , Relação Estrutura-AtividadeRESUMO
A knowledge based approach has been adopted to identify novel NOP receptor agonists with simplified hydrophobes. Substitution of the benzimidazol-2-one piperidine motif with a range of hydrophobic groups and pharmacophore guided bio-isosteric replacement of the benzimidazol-2-one moiety was explored. Compound 51 was found to be a high affinity, potent NOP receptor agonist with reduced affinity for the hERG channel.
Assuntos
Benzimidazóis/química , Antagonistas de Entorpecentes/química , Piperidinas/química , Animais , Cricetinae , Receptores Opioides/metabolismo , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.
Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Modelos Animais de Doenças , Cães , Humanos , Células Madin Darby de Rim Canino , Camundongos , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Estudo de Prova de ConceitoRESUMO
The N-3 position of a series of 3-phenoxypropyl piperidine benzimidazol-2-one analogues was optimised using the predictive power of a CoMFA model. The model was used to prioritise compounds for synthesis culminating in the triazole (+)-24. (+)-24 was found to be a high affinity, potent NOP agonist and demonstrated both antinociceptive and antiallodynic effects when administered iv to rodents.
Assuntos
Benzimidazóis/química , Modelos Moleculares , Receptores Opioides/agonistas , Analgésicos/química , Animais , Benzimidazóis/farmacologia , Hipnóticos e Sedativos/química , Roedores , Relação Estrutura-Atividade , Receptor de NociceptinaRESUMO
Potent and selective class IIa HDAC tetrasubstituted cyclopropane hydroxamic acid inhibitors were identified with high oral bioavailability that exhibited good brain and muscle exposure. Compound 14 displayed suitable properties for assessment of the impact of class IIa HDAC catalytic site inhibition in preclinical disease models.
RESUMO
Protein kinases constitute an attractive family of enzyme targets with high relevance to cell and disease biology. Small molecule inhibitors are powerful tools to dissect and elucidate the function of kinases in chemical biology research and to serve as potential starting points for drug discovery. However, the discovery and development of novel inhibitors remains challenging. Here, we describe a structure-based de novo design approach that generates novel, hinge-binding fragments that are synthetically feasible and can be elaborated to small molecule libraries. Starting from commercially available compounds, core fragments were extracted, filtered for pharmacophoric properties compatible with hinge-region binding, and docked into a panel of protein kinases. Fragments with a high consensus score were subsequently short-listed for synthesis. Application of this strategy led to a number of core fragments with no previously reported activity against kinases. Small libraries around the core fragments were synthesized, and representative compounds were tested against a large panel of protein kinases and subjected to co-crystallization experiments. Each of the tested compounds was active against at least one kinase, but not all kinases in the panel were inhibited. A number of compounds showed high ligand efficiencies for therapeutically relevant kinases; among them were MAPKAP-K3, SRPK1, SGK1, TAK1, and GCK for which only few inhibitors are reported in the literature.
Assuntos
Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/química , Sítios de Ligação , Proteína Tirosina Quinase CSK , Simulação por Computador , Cristalografia por Raios X , Proteínas Imediatamente Precoces/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , MAP Quinase Quinase Quinases/antagonistas & inibidores , Simulação de Acoplamento Molecular , Estrutura Molecular , Conformação Proteica , Inibidores de Proteínas Quinases/metabolismo , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/farmacologia , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/químicaRESUMO
Inhibition of class IIa histone deacetylase (HDAC) enzymes have been suggested as a therapeutic strategy for a number of diseases, including Huntington's disease. Catalytic-site small molecule inhibitors of the class IIa HDAC4, -5, -7, and -9 were developed. These trisubstituted diarylcyclopropanehydroxamic acids were designed to exploit a lower pocket that is characteristic for the class IIa HDACs, not present in other HDAC classes. Selected inhibitors were cocrystallized with the catalytic domain of human HDAC4. We describe the first HDAC4 catalytic domain crystal structure in a "closed-loop" form, which in our view represents the biologically relevant conformation. We have demonstrated that these molecules can differentiate class IIa HDACs from class I and class IIb subtypes. They exhibited pharmacokinetic properties that should enable the assessment of their therapeutic benefit in both peripheral and CNS disorders. These selective inhibitors provide a means for evaluating potential efficacy in preclinical models in vivo.