RESUMO
AIM: To describe the biomarker strategy that was applied to select survodutide (BI 456906), BI 456908 and BI 456897 from 19 dual glucagon receptor (GCGR)/ glucagon-like peptide-1 receptor (GLP-1R) agonists for in-depth pharmacological profiling, which led to the qualification of survodutide as the clinical development candidate. MATERIALS AND METHODS: Potencies to increase cyclic adenosine monophosphate (cAMP) were determined in Chinese hamster ovary (CHO)-K1 cells stably expressing human GCGR and GLP-1R. Agonism for endogenously expressed receptors was investigated in insulinoma cells (MIN6) for mouse GLP-1R, and in rat primary hepatocytes for the GCGR. In vivo potencies to engage the GLP-1R or GCGR were determined, measuring improvement in oral glucose tolerance (30 nmol/kg) and increase in plasma fibroblast growth factor-21 (FGF21) and liver nicotinamide N-methyltransferase (NNMT) mRNA expression (100 nmol/kg), respectively. Body weight- and glucose-lowering efficacies were investigated in diet-induced obese (DIO) mice and diabetic db/db mice, respectively. RESULTS: Upon acute dosing in lean mice, target engagement biomarkers for the GCGR and GLP-1R demonstrated a significant correlation (Spearman correlation coefficient with p < 0.05) to the in vitro GCGR and GLP-1R potencies for the 19 dual agonists investigated. Survodutide, BI 456908 and BI 456897 were selected for in-depth pharmacological profiling based on the significant improvement in acute oral glucose tolerance achieved (area under the curve [AUC] of 54%, 57% and 60% vs. vehicle) that was comparable to semaglutide (AUC of 45% vs. vehicle), while showing different degrees of in vivo GCGR engagement, as determined by hepatic NNMT mRNA expression (increased by 15- to 17-fold vs. vehicle) and plasma FGF21 concentrations (increased by up to sevenfold vs. vehicle). In DIO mice, survodutide (30 nmol/kg/once daily), BI 456908 (30 nmol/kg/once daily) and BI 456897 (10 nmol/kg/once daily) achieved a body weight-lowering efficacy from baseline of 25%, 27% and 26%, respectively. In db/db mice, survodutide and BI 456908 (10 and 20 nmol/kg/once daily) significantly lowered glycated haemoglobin (0.4%-0.6%); no significant effect was observed for BI 456897 (3 and 7 nmol/kg/once daily). CONCLUSIONS: Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, engaging the GCGR for robust body weight-lowering efficacy exceeding that of selective GLP-1R agonists, while achieving antidiabetic efficacy that was comparable to selective GLP-1R agonism. Survodutide is currently being investigated in Phase 3 clinical trials in people living with obesity.
Assuntos
Cricetulus , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes , Receptores de Glucagon , Animais , Receptores de Glucagon/agonistas , Receptores de Glucagon/genética , Camundongos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Células CHO , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Humanos , Biomarcadores/sangue , Masculino , Ratos , Camundongos Obesos , Camundongos Endogâmicos C57BL , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológicoRESUMO
The benzimidazole core is a common moiety in a large number of natural products and pharmacologically active small molecules. The synthesis of novel benzimidazole derivatives remains a main focus in medicinal research. In continuation of the efforts towards Ce(III) catalysts for organic transformations, we observed for the first time the activity of the iodide ion and copper cation in activating CeCl3·7H2O in the selective formation of prototypical 2-substituted benzimidazoles. The one-pot CeCl3·7H2O-CuI catalytic system procedure includes the cyclo-dehydrogenation of aniline Schiff's bases, generated in situ from the condensation of 1,2-phenylenediamine and aldehydes, followed by the oxidation with iodine, which works as a hydrogen sponge. Mild reaction conditions, good to excellent yields, and clean reactions make the procedure a useful contribution to the synthesis of biologically active fused heterocycles containing benzimidazoquinazolines.
Assuntos
Benzimidazóis/química , Técnicas de Química Analítica/métodos , Quinazolinas/síntese química , Compostos de Anilina/química , Catálise , Estrutura Molecular , Quinazolinas/química , Bases de Schiff/químicaRESUMO
Insulin-regulated aminopeptidase (IRAP) is an enzyme with important biological functions and the target of drug-discovery efforts. We combined in silico screening with a medicinal chemistry optimization campaign to discover a nanomolar inhibitor of IRAP based on a pyrazolylpyrimidine scaffold. This compound displays an excellent selectivity profile versus homologous aminopeptidases, and kinetic analysis suggests it utilizes an uncompetitive mechanism of action when inhibiting the cleavage of a typical dipeptidic substrate. Surprisingly, the compound is a poor inhibitor of the processing of the physiological cyclic peptide substrate oxytocin and a 10mer antigenic epitope precursor but displays a biphasic inhibition profile for the trimming of a 9mer antigenic peptide. While the compound reduces IRAP-dependent cross-presentation of an 8mer epitope in a cellular assay, it fails to block in vitro trimming of select epitope precursors. To gain insight into the mechanism and basis of this unusual selectivity for this inhibitor, we solved the crystal structure of its complex with IRAP. The structure indicated direct zinc(II) engagement by the pyrazolylpyrimidine scaffold and revealed that the compound binds to an open conformation of the enzyme in a pose that should block the conformational transition to the enzymatically active closed conformation previously observed for other low-molecular-weight inhibitors. This compound constitutes the first IRAP inhibitor targeting the active site that utilizes a conformation-specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements.
Assuntos
Cistinil Aminopeptidase , Cistinil Aminopeptidase/antagonistas & inibidores , Cistinil Aminopeptidase/química , Cistinil Aminopeptidase/metabolismo , Humanos , Cristalografia por Raios X , Especificidade por Substrato , Pirimidinas/química , Pirimidinas/farmacologia , Modelos Moleculares , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Conformação ProteicaRESUMO
Mixed Lineage Kinase domain-Like pseudokinase (MLKL) is implicated in a broad range of diseases due to its role as the ultimate effector of necroptosis and has therefore emerged as an attractive drug target. Here, we describe the development of PROteolysis TArgeting Chimeras (PROTACs) as a novel approach to knock down MLKL through chemical means. A series of candidate degraders were synthesized from a high-affinity pyrazole carboxamide-based MLKL ligand leading to the identification of a PROTAC molecule that effectively degraded MLKL and completely abrogated cell death in a TSZ model of necroptosis. By leveraging the innate ability of these PROTACs to degrade MLKL in a dose-dependent manner, the quantitative relationship between MLKL levels and necroptosis was interrogated. This work demonstrates the feasibility of targeting MLKL using a PROTAC approach and provides a powerful tool to further our understanding of the role of MLKL within the necroptotic pathway.
Assuntos
Necroptose , Proteínas Quinases , Quimera de Direcionamento de Proteólise , Apoptose , Morte Celular , Necroptose/efeitos dos fármacos , Proteínas Quinases/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Quimera de Direcionamento de Proteólise/química , Quimera de Direcionamento de Proteólise/farmacologiaRESUMO
OBJECTIVE: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906. METHODS: BI 456906 was characterized using cell-based in vitro assays to determine functional agonism. In vivo pharmacological studies were performed using acute and subchronic dosing regimens to demonstrate target engagement for the GCGR and GLP-1R, and weight lowering efficacy. RESULTS: BI 456906 is a potent, acylated peptide containing a C18 fatty acid as a half-life extending principle to support once-weekly dosing in humans. Pharmacological doses of BI 456906 provided greater bodyweight reductions in mice compared with maximally effective doses of the GLP-1R agonist semaglutide. BI 456906's superior efficacy is the consequence of increased energy expenditure and reduced food intake. Engagement of both receptors in vivo was demonstrated via glucose tolerance, food intake, and gastric emptying tests for the GLP-1R, and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (amino acids, fibroblast growth factor-21) for the GCGR. The dual activity of BI 456906 at the GLP-1R and GCGR was supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay. CONCLUSIONS: BI 456906 is a potent GCGR/GLP-1R dual agonist with robust anti-obesity efficacy achieved by increasing energy expenditure and decreasing food intake.
Assuntos
Peptídeo 1 Semelhante ao Glucagon , Receptores de Glucagon , Animais , Humanos , Camundongos , Peptídeo 1 Semelhante ao Glucagon/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Oxintomodulina/farmacologia , Peptídeos/farmacologia , Peptídeos/metabolismo , Receptores de Glucagon/metabolismoRESUMO
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
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.
Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Encéfalo/metabolismoRESUMO
The lead optimization process to identify new selective dopamine D(3) receptor antagonists is reported. DMPK parameters and binding data suggest that selective D(3) receptor antagonists as potential PET ligands might have been identified.
Assuntos
Imidazolidinas/química , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Encéfalo/efeitos dos fármacos , Química Orgânica/métodos , Química Farmacêutica/métodos , Antagonistas dos Receptores de Dopamina D2 , Humanos , Imidazolidinas/síntese química , Imidazolidinas/farmacologia , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Tomografia por Emissão de Pósitrons , Ratos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Relação Estrutura-Atividade , SuínosRESUMO
The synthesis and the SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The new scaffolds of the [g]-fused and the hetero-fused tricyclic benzazepine are here reported together with their pharmacokinetic profile.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The synthesis and SAR of a new series of potent and selective dopamine D(3) receptor antagonists is reported. The introduction of a tricyclic [h]-fused benzazepine moiety on the recently disclosed scaffold of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines is reported. A full rat pharmacokinetic characterization is also reported.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Benzazepinas/química , Técnicas de Química Combinatória , Antagonistas de Dopamina/química , Desenho de Fármacos , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.
Assuntos
Benzazepinas/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/síntese química , Acetilcolina/metabolismo , Administração Oral , Consumo de Bebidas Alcoólicas/prevenção & controle , Animais , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3/agonistas , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tabagismo/prevenção & controle , Triazóis/farmacocinética , Triazóis/farmacologiaAssuntos
Aminoácido Oxirredutases/farmacologia , Antifibróticos/farmacologia , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/normas , Aminoácido Oxirredutases/análise , Aminoácido Oxirredutases/uso terapêutico , Antifibróticos/análise , Antifibróticos/uso terapêutico , Técnicas Biossensoriais/métodos , Fibrose/tratamento farmacológico , Fibrose/prevenção & controle , HumanosRESUMO
[reaction: see text] Titanium(IV) benzylidenes bearing a masked nitrogen nucleophile in the ortho position converted Merrifield resin-bound esters into enol ethers. An unusual nitrogen protecting group, N-silylated tert-butyl carbamate, was employed. One percent TFA released N-Boc indoles in high yield and purity. N-Methyl indoles were also prepared. Cyclative termination was not required to release the chameleon catch. The first example of a carbonyl group within a titanium alkylidene reagent is reported.
RESUMO
A series of 1,1'-spiro-substituted hexahydrofuroquinoline derivatives exhibiting potent cholesteryl ester transfer protein (CETP) inhibition at reduced lipophilicity was identified. A focused structure-activity relationship (SAR) exploration led to the potent and comparatively polar CETP inhibitor 26 showing robust high density lipoprotein-cholesterol (HDL-C) elevation and low density lipoprotein-cholesterol (LDL-C) reduction in transgenic hCETP/hApoB-100 mice. Compound 26 was also shown to positively differentiate from highly lipophilic CETP inhibitors in its complete elimination from fat tissue in hCETP transgenic mice as evident within 21 days after cessation of treatment. In addition, compound 26 showed no significant effects on aldosterone secretion from H295R cells, as well as no significant effects on blood pressure and electrocardiogram parameters in telemetrized cynomolgus monkeys.
Assuntos
Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Hidroxiquinolinas/síntese química , Quinolinas/síntese química , Compostos de Espiro/síntese química , Animais , Anticolesterolemiantes/síntese química , Anticolesterolemiantes/farmacocinética , Anticolesterolemiantes/farmacologia , HDL-Colesterol/sangue , Humanos , Hidroxiquinolinas/farmacocinética , Hidroxiquinolinas/farmacologia , Macaca fascicularis , Camundongos Transgênicos , Quinolinas/farmacocinética , Quinolinas/farmacologia , Compostos de Espiro/farmacocinética , Compostos de Espiro/farmacologia , Relação Estrutura-AtividadeRESUMO
The discovery of new highly potent and selective dopamine (DA) D(3) receptor antagonists has recently allowed the characterization of the DA D(3) receptor in a range of preclinical animal models of drug addiction. A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes, members of which showed a high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles, is reported here. Members of a group of derivatives from this series showed good oral bioavailability and brain penetration and very high in vitro affinity and selectivity for the DA D(3) receptor, as well as high in vitro potency for antagonism at this receptor. Several members of this series also significantly attenuate the expression of conditioned place preference (CPP) to nicotine and cocaine.
Assuntos
Hexanos/química , Hexanos/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Animais , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Simulação por Computador , Desenho de Fármacos , Cobaias , Humanos , Masculino , Modelos Animais , Modelos Químicos , Estrutura Molecular , Receptores de Dopamina D3/biossíntese , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Design, synthesis and properties of a new tricyclic series of selective 5-HT2C receptor antagonists are reported. Conformational analysis of a 2-phenyl-dihydropyrrolone scaffold suggested that ring fusion, locking coplanarity between the rings of this moiety, might be tolerated by the 5-HT2C receptor. An interesting effect of this is the change of the nature of the carbon-carbon double bond of the lactam ring from vinylic to aromatic. The changes were found to result in a favourable profile at both, receptor and in vivo level.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Alquilação , Animais , Disponibilidade Biológica , Desenho de Fármacos , Compostos Heterocíclicos/farmacocinética , Humanos , Indicadores e Reagentes , Masculino , Modelos Moleculares , Conformação Molecular , Ratos , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2B de Serotonina/efeitos dos fármacos , Relação Estrutura-AtividadeRESUMO
Two independent approaches resulted in the identification of a series of isoindolone derivatives as potent and selective 5-HT2C antagonists. From a Medicinal Chemistry perspective this template was considered interesting as it allowed the incorporation of the carbon-carbon double bond of an earlier dihydropyrrolone series in an aromatic system within a comparatively simple and compact motif. Additionally an in silico screening approach of the corporate database using a 5-HT2C pharmacophore model resulted in the identification of a related structure containing this template. The strategy used to optimise potency at the target receptor and to improve the pharmacokinetic profile is described, resulting in molecules combining high potency with good selectivity and oral bioavailability.
Assuntos
Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/farmacologia , Indóis/síntese química , Indóis/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Animais , Disponibilidade Biológica , Bases de Dados Factuais , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Isoindóis , Masculino , Ratos , Relação Estrutura-AtividadeRESUMO
Within the continuous quest for the discovery of novel compounds able to treat anxiety and depression, the generation of a pharmacophore model for 5-HT2C receptor antagonists and the discovery of a new class of potent and selective 5-HT2C molecules are reported.
Assuntos
Pirróis/síntese química , Pirróis/farmacologia , Pirrolidinonas/síntese química , Pirrolidinonas/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/síntese química , Antagonistas da Serotonina/farmacologia , Modelos MolecularesRESUMO
A strategy of systematically targeting more rigid analogues of the known MCH R1 receptor antagonist, SB-568849, serendipitously uncovered a binding mode accessible to N-aryl-phthalimide ligands. Optimisation to improve the stability of this compound class led to the discovery of novel N-aryl-quinazolinones, benzotriazinones and thienopyrimidinones as selective ligands with good affinity for human melanin-concentrating hormone receptor 1.
Assuntos
Amidas/farmacologia , Compostos de Bifenilo/farmacologia , Receptores de Somatostatina/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Anilidas/química , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/química , Humanos , Estrutura Molecular , Receptores de Somatostatina/metabolismo , Relação Estrutura-AtividadeRESUMO
Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog.