RESUMO
A new series of in vitro potent and highly selective histone methyl transferase enzyme G9a inhibitors was obtained. In particular, compound 2a, one the most potent G9a inhibitor identified, was endowed with >130-fold selectivity over GLP and excellent ligand efficiency. Therefore, it may represent a valuable tool compound to validate the role of highly selective G9a inhibitors in different pathological conditions. When 2a was characterized in vitro in cellular models of skeletal muscle differentiation, a relevant increase of myofibers' size and reduction of the fibroadipogenic infiltration were observed, further confirming the therapeutic potential of selective G9a inhibitors for the treatment of Duchenne muscle dystrophy.
Assuntos
Histona-Lisina N-Metiltransferase , Histonas , Inibidores Enzimáticos/farmacologiaRESUMO
Chronic hepatitis B (CHB) is a major worldwide public health problem and novel anti-HBV therapies preventing liver disease progression to cirrhosis and hepatocellular carcinoma are urgently needed. Over the last several years, capsid assembly modulators (CAM) have emerged as clinically effective anti-HBV agents which can inhibit HBV replication in CHB patients. As part of a drug discovery program aimed at obtaining novel CAM endowed with high in vitro and in vivo antiviral activity, we identified a novel series of sulfamoylbenzamide (SBA) derivatives. Compound 10, one of the most in vitro potent SBA-derived CAM discovered to date, showed excellent pharmacokinetics in mice suitable for oral dosing. When studied in a transgenic mouse model of hepatic HBV replication, it was considerably more potent than NVR 3-778, the first sulfamoylbenzamide (SBA) CAM that entered clinical trials for CHB, at reducing viral replication in a dose-dependent fashion. We present herein the discovery process, the SAR analysis and the pre-clinical profile of this novel SBA CAM.
Assuntos
Antivirais , Capsídeo , Animais , Antivirais/farmacocinética , Proteínas do Capsídeo , Vírus da Hepatite B , Camundongos , Montagem de Vírus , Replicação ViralRESUMO
The last two decades have provided a large weight of preclinical data implicating the neurokinin-1 receptor (NK1) and its cognate ligand substance P (SP) in a broad range of both central and peripheral disease conditions. However, to date, only the NK1 receptor antagonist aprepitant has been approved as a therapeutic and this is to prevent chemotherapy-induced nausea & vomiting (CINV). The belief remained that the full therapeutic potential of NK1 receptor antagonists had yet to be realized; therefore clinical evidence that NK1 receptor antagonists may be effective in major depression disorder, resulted in a significant further investment in discovering novel CNS penetrant druggable NK1 receptor antagonists to address this condition. At GlaxoSmithKline after the discovery of casopitant, that went on to demonstrate efficacy as a novel antidepressant in the clinic, additional novel analogues of this NK1 receptor antagonist were designed to further enhance its drug developability characteristics. Herein, we therefore describe the discovery process and the vivo pharmacological and pharmacokinetic profile of the new NK1 receptor antagonist 3a (also called orvepitant), selected as clinical candidate and further progressed into clinical studies for major depressive disorder. Moreover, molecular modeling studies enabled us to improve the pharmacophore model of the NK1 receptor antagonists with the identification of a region able to accommodate a variety of heterocycle moieties.
Assuntos
Antidepressivos/química , Antagonistas dos Receptores de Neurocinina-1/química , Receptores da Neurocinina-1/química , Animais , Antidepressivos/síntese química , Antidepressivos/farmacocinética , Comportamento Animal/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/síntese química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Compostos Bicíclicos Heterocíclicos com Pontes/farmacocinética , Células CHO , Cricetinae , Cricetulus , Cães , Feminino , Gerbillinae , Meia-Vida , Humanos , Masculino , Modelos Moleculares , Conformação Molecular , Antagonistas dos Receptores de Neurocinina-1/síntese química , Antagonistas dos Receptores de Neurocinina-1/farmacocinética , Piperazinas/química , Piperidinas/síntese química , Piperidinas/química , Piperidinas/farmacocinética , Ligação Proteica , Ratos , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/metabolismoRESUMO
Src homology 2-containing protein tyrosine phosphatase 2 (SHP2) is the first reported nonreceptor oncogenic tyrosine phosphatase connecting multiple signal transduction cascades and exerting immunoinhibitory function through the PD-1 checkpoint receptor. As part of a drug discovery program aimed at obtaining novel allosteric SHP2 inhibitors, a series of pyrazopyrazine derivatives bearing an original bicyclo[3.1.0]hexane basic moiety on the left-hand side region of the molecule were identified. We report herein the discovery process, the in vitro pharmacological profile, and the early developability features of compound 25, one of the most potent members of the series.
RESUMO
Two complementary stereospecific synthetic approaches for the preparation of unsymmetrical ortho-substituted N-(4,4-diphenylbut-3-enyl) derivatives of nipecotic acid are described. Determination of the activity of the prepared compounds at the GAT-1 transporter highlighted differing SAR requirements of the E- and Z-phenyl rings, and led to the discovery of a compound with comparable potency to tiagabine. Some attempts to replace nipecotic acid with alternative novel amino acids are also described.
Assuntos
Proteínas da Membrana Plasmática de Transporte de GABA/química , Inibidores da Captação de GABA/síntese química , Ácidos Nipecóticos/síntese química , Proteínas da Membrana Plasmática de Transporte de GABA/metabolismo , Inibidores da Captação de GABA/química , Inibidores da Captação de GABA/farmacologia , Ácidos Nipecóticos/química , Ácidos Nipecóticos/farmacologia , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX(1) and the OX(2) receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX(1) receptor is highly expressed throughout the hypothalamus, whilst the OX(2) receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX(1) and OX(2) receptor antagonists, highly effective in a pre-clinical model of sleep.
Assuntos
Descoberta de Drogas , Piperidinas/farmacologia , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Transtornos do Sono-Vigília/tratamento farmacológico , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Modelos Moleculares , Estrutura Molecular , Receptores de Orexina , Piperidinas/síntese química , Piperidinas/química , Ratos , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Further exploration around the recently disclosed potent triple re-uptake inhibitor 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptane led to the identification of a new series of potent triple re-uptake inhibitors endowed with good developability characteristics. The insertion of a further aryl moiety into the template allowed the 'titration' of the SERT/NET/DAT ratio leading to the identification of further tools in this important area.
Assuntos
Inibidores da Captação Adrenérgica/química , Inibidores da Captação de Dopamina/química , Heptanos/química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Compostos Aza/química , Compostos Bicíclicos com Pontes/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Inibidores da Captação de Dopamina/síntese química , Inibidores da Captação de Dopamina/farmacologia , Heptanos/síntese química , Heptanos/farmacologia , Humanos , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ligação Proteica , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
H3K9 methylation maintains cell identity orchestrating stable silencing and anchoring of alternate fate genes within the heterochromatic compartment underneath the nuclear lamina (NL). However, how cell type-specific genomic regions are specifically targeted to the NL is still elusive. Using fibro-adipogenic progenitors (FAPs) as a model, we identified Prdm16 as a nuclear envelope protein that anchors H3K9-methylated chromatin in a cell-specific manner. We show that Prdm16 mediates FAP developmental capacities by orchestrating lamina-associated domain organization and heterochromatin sequestration at the nuclear periphery. We found that Prdm16 localizes at the NL where it cooperates with the H3K9 methyltransferases G9a/GLP to mediate tethering and silencing of myogenic genes, thus repressing an alternative myogenic fate in FAPs. Genetic and pharmacological disruption of this repressive pathway confers to FAP myogenic competence, preventing fibro-adipogenic degeneration of dystrophic muscles. In summary, we reveal a druggable mechanism of heterochromatin perinuclear sequestration exploitable to reprogram FAPs in vivo.
RESUMO
A new class of selective orexin 2 antagonist was identified among commercial products. Initial SAR was obtained using commercial derivatives only prior to starting ad hoc medicinal chemistry activities.
Assuntos
Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores de Neuropeptídeos/antagonistas & inibidores , Triazóis/farmacologia , Animais , Humanos , Modelos Moleculares , Receptores de Orexina , Ratos , Relação Estrutura-Atividade , Triazóis/químicaRESUMO
A new class of azabicyclo[3.1.0]benzenesulfonamides is presented as selective dopamine D3 antagonists together with SAR and selectivity data.
Assuntos
Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Receptores de Dopamina D3/metabolismo , Sulfonamidas/química , Sulfonamidas/farmacologia , Benzeno/química , Benzeno/farmacologia , Humanos , Relação Estrutura-AtividadeRESUMO
A focused exploration targeting conformationally restricted analogues of Vestipitant, resulted in the discovery of novel, in vitro potent NK(1) antagonists. In particular, two of the compounds reported exhibited a good pharmacokinetic (PK) profile and produced anxiolytic-like effects in the gerbil foot tapping (GFT) in vivo model.
Assuntos
Ansiolíticos/síntese química , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/síntese química , Ansiolíticos/química , Ansiolíticos/farmacocinética , Desenho de Fármacos , Fluorbenzenos , Humanos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacocinética , Receptores da Neurocinina-1/metabolismoRESUMO
A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.
Assuntos
Compostos Azabicíclicos/química , Imidazóis/química , Neuropeptídeos/antagonistas & inibidores , Piperidinas/química , Animais , Simulação por Computador , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Microssomos Hepáticos/metabolismo , Neuropeptídeos/metabolismo , Ratos , TermodinâmicaRESUMO
Novel series of pyrrole-pyrazinone and pyrazole-pyrazinone have been identified as potent and selective Vasopressin(1b) receptor antagonists. Exploration of the substitution pattern around the core of these templates allowed generation of compounds with high inhibitory potency at the Vasopressin(1b) receptor, including examples that showed good selectivity with respect to Vasopressin(1a), Vasopressin(2), and Oxytocin receptor subtypes.
Assuntos
Antagonistas dos Receptores de Hormônios Antidiuréticos , Pirazinas/farmacologia , Pirróis/farmacologia , Pirazinas/química , Pirróis/química , Relação Estrutura-AtividadeRESUMO
A novel imidazobenzazepine template (5a) with potent dual H(1)/5-HT(2A) antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R(1)-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H(1)/5-HT(2A) receptor antagonist activities and good developability profiles.
Assuntos
Receptor 5-HT1A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/uso terapêutico , Transtornos do Sono-Vigília/tratamento farmacológico , HumanosRESUMO
A novel class of small molecule NPY Y5 antagonists based around an azabicyclo[3.1.0]hexane scaffold was identified through modification of a screening hit. Structure-activity relationships and efforts undertaken to achieve a favourable pharmacokinetic profile in rat are described.
Assuntos
Aminas/química , Compostos Azabicíclicos/química , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Aminas/síntese química , Aminas/farmacocinética , Animais , Linhagem Celular , Humanos , Ratos , Receptores de Neuropeptídeo Y/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A novel class of benzimidazole NPY Y5 receptor antagonists was prepared exploiting a privileged spirocarbamate moiety. The structure-activity relationship of this series and efforts to achieve a profile suitable for further development and an appropriate pharmacokinetic profile in rat are described. Optimisation led to the identification of the brain penetrant, orally bioavailable Y5 antagonist 9b which significantly inhibited the food intake induced by a Y5 selective agonist with a minimal effective dose of 30mg/kg po.
Assuntos
Benzimidazóis/química , Benzimidazóis/farmacologia , Desenho de Fármacos , Ingestão de Alimentos/efeitos dos fármacos , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Administração Oral , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacocinética , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Ratos , Relação Estrutura-AtividadeRESUMO
A novel series of trans-8-aminomethyl-1-oxa-3-azaspiro[4.5]decan-2-one derivatives was identified with potent NPY Y5 antagonist activity. Optimization of the original lead furnished compounds 23p and 23u, which combine sub-nanomolar Y5 activity with metabolic stability, oral bioavailability, brain penetration and strong preclinical profile for development. Both compounds significantly inhibited the food intake induced by a Y5 selective agonist with minimal effective doses of 3mg/kg po.
Assuntos
Carbamatos/química , Carbamatos/farmacologia , Receptores de Neuropeptídeo Y/antagonistas & inibidores , Receptores de Neuropeptídeo Y/metabolismo , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Animais , Carbamatos/metabolismo , Carbamatos/farmacocinética , Linhagem Celular , Inibidores das Enzimas do Citocromo P-450 , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Microssomos Hepáticos/metabolismo , Ratos , Compostos de Espiro/metabolismo , Compostos de Espiro/farmacocinética , Relação Estrutura-AtividadeRESUMO
5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.
Assuntos
Quinolonas/química , Receptores 5-HT1 de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Animais , Autorreceptores/antagonistas & inibidores , Autorreceptores/efeitos dos fármacos , Quinolonas/farmacocinética , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sinapses/químicaRESUMO
Antagonists of the corticotropin-releasing factor (CRF) neuropeptide may prove effective in treating stress and anxiety related disorders. In an effort to identify antagonists with improved physico-chemical properties a new series of CRF(1) antagonists were designed to substitute the propyl groups at the C7 position of the pyrazolo[1,5-a]pyrimidine core of 1 with heterocycles. Compound (S)-8d was identified as a high affinity ligand with a pK(i) value of 8.2 and a functional CRF(1) antagonist with pIC(50) value of 7.0 in the in vitro CRF ACTH production assay.
Assuntos
Compostos Azabicíclicos/química , Oxidiazóis/química , Pirazóis/química , Piridinas/química , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Compostos Azabicíclicos/síntese química , Compostos Azabicíclicos/farmacocinética , Humanos , Microssomos Hepáticos/metabolismo , Oxidiazóis/síntese química , Oxidiazóis/farmacocinética , Ligação Proteica , Receptores de Hormônio Liberador da Corticotropina/genética , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMO
The identification of a highly selective D(2) partial agonist, D(3) antagonist tool molecule which demonstrates high levels of brain exposure and selectivity against an extensive range of dopamine, serotonin, adrenergic, histamine, and muscarinic receptors is described.