RESUMO
G-protein coupled receptor kinase 2 (GRK2), which is upregulated in the failing heart, appears to play a critical role in heart failure (HF) progression in part because enhanced GRK2 activity promotes dysfunction of ß-adrenergic signaling and myocyte death. An orally bioavailable GRK2 inhibitor could offer unique therapeutic outcomes that cannot be attained by current heart failure treatments that directly target GPCRs or angiotensin-converting enzyme. Herein, we describe the discovery of a potent, selective, and orally bioavailable GRK2 inhibitor, 8h, through high-throughput screening, hit-to-lead optimization, structure-based design, molecular modelling, synthesis, and biological evaluation. In the cellular target engagement assays, 8h enhances isoproterenol-mediated cyclic adenosine 3',5'-monophosphate (cAMP) production in HEK293 cells overexpressing GRK2. Compound 8h was further evaluated in a human stem cell-derived cardiomyocyte (HSC-CM) contractility assay and potentiated isoproterenol-induced beating rate in HSC-CMs.
Assuntos
Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Ftalazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Animais , Ensaios Enzimáticos , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Células HEK293 , Humanos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Estrutura Molecular , Miócitos Cardíacos/efeitos dos fármacos , Ftalazinas/síntese química , Ftalazinas/farmacocinética , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacocinética , Quinazolinas/síntese química , Quinazolinas/metabolismo , Quinazolinas/farmacocinética , Relação Estrutura-AtividadeRESUMO
Type 2 diabetes mellitus (T2DM) is characterized by chronically elevated plasma glucose levels. The inhibition of glucagon-induced hepatic glucose output via antagonism of the glucagon receptor (GCGR) using a small-molecule antagonist is a promising mechanism for improving glycemic control in the diabetic state. The present work discloses the discovery of indazole-based ß-alanine derivatives as potent GCGR antagonists through an efficient enantioselective synthesis and structure-activity relationship (SAR) exploration and optimization. Compounds within this class exhibited excellent pharmacokinetic properties in multiple preclinical species. In an acute dog glucagon challenge test, compound 13K significantly inhibited glucagon-mediated blood glucose increase when dosed orally at 10â¯mg/kg.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/síntese química , Indazóis/química , Receptores de Glucagon/antagonistas & inibidores , beta-Alanina/síntese química , Sequência de Aminoácidos , Animais , Glicemia/efeitos dos fármacos , Metabolismo dos Carboidratos , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Humanos , Hipoglicemiantes/farmacocinética , Fígado/metabolismo , Camundongos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Ratos , Relação Estrutura-Atividade , beta-Alanina/farmacocinéticaRESUMO
A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.
Assuntos
Indazóis/química , Receptores de Glucagon/antagonistas & inibidores , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Computer-aided drug discovery activities at Janssen are carried out by scientists in the Computational Chemistry group of the Discovery Sciences organization. This perspective gives an overview of the organizational and operational structure, the science, internal and external collaborations, and the impact of the group on Drug Discovery at Janssen.
Assuntos
Desenho Assistido por Computador , Descoberta de Drogas/métodos , Indústria Farmacêutica/métodos , Modelos Moleculares , Química Farmacêutica , Biologia Computacional , Desenho de Fármacos , Pesquisa , SoftwareRESUMO
In May and August, 2016, several pharmaceutical companies convened to discuss and compare experiences with Free Energy Perturbation (FEP). This unusual synchronization of interest was prompted by Schrödinger's FEP+ implementation and offered the opportunity to share fresh studies with FEP and enable broader discussions on the topic. This article summarizes key conclusions of the meetings, including a path forward of actions for this group to aid the accelerated evaluation, application and development of free energy and related quantitative, structure-based design methods.
Assuntos
Descoberta de Drogas/métodos , Preparações Farmacêuticas/química , Desenho de Fármacos , Indústria Farmacêutica , Humanos , Estrutura Molecular , Software , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Acid-sensing ion channels (ASICs) are proton-gated cation channels widely expressed in the nervous system. ASIC gating is modulated by divalent cations as well as small molecules; however, the molecular determinants of gating modulation by divalent cations are not well understood. Previously, we identified two small molecules that bind to ASIC1a at a novel site in the acidic pocket and modulate ASIC1 gating in a manner broadly resembling divalent cations, raising the possibility that these small molecules may help to illuminate the molecular determinants of gating modulation by divalent cations. Here, we examined how these two groups of modulators might interact as well as mutational effects on ASIC1a gating and its modulation by divalent cations. Our results indicate that binding of divalent cations to an acidic pocket site plays a key role in gating modulation of the channel.
Assuntos
Canais Iônicos Sensíveis a Ácido , Prótons , Cátions Bivalentes/metabolismo , Canais Iônicos Sensíveis a Ácido/metabolismo , MutaçãoRESUMO
Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.
Assuntos
Amidas/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Animais , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Ratos , Ratos Sprague-Dawley , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Activated factor XI (FXIa) inhibitors are promising novel anticoagulants with low bleeding risk compared with current anticoagulants. The discovery of potent FXIa inhibitors with good oral bioavailability has been challenging. Herein, we describe our discovery effort, utilizing nonclassical interactions to improve potency, cellular permeability, and oral bioavailability by enhancing the binding while reducing polar atoms. Beginning with literature-inspired pyridine N-oxide-based FXIa inhibitor 1, the imidazole linker was first replaced with a pyrazole moiety to establish a polar C-H···water hydrogen-bonding interaction. Then, structure-based drug design was employed to modify lead molecule 2d in the P1' and P2' regions, with substituents interacting with key residues through various nonclassical interactions. As a result, a potent FXIa inhibitor 3f (Ki = 0.17 nM) was discovered. This compound demonstrated oral bioavailability in preclinical species (rat 36.4%, dog 80.5%, and monkey 43.0%) and displayed a dose-dependent antithrombotic effect in a rabbit arteriovenous shunt model of thrombosis.
Assuntos
Fator XIa , Piridinas , Animais , Anticoagulantes/química , Anticoagulantes/farmacologia , Cães , Desenho de Fármacos , Fator XIa/metabolismo , Piridinas/farmacologia , Coelhos , RatosRESUMO
Background: Accurate prediction of absorption, distribution, metabolism and excretion (ADME) properties can facilitate the identification of promising drug candidates. Methodology & Results: The authors present the Janssen generic Target Product Profile (gTPP) model, which predicts 18 early ADME properties, employs a graph convolutional neural network algorithm and was trained on between 1000-10,000 internal data points per predicted parameter. gTPP demonstrated stronger predictive power than pretrained commercial ADME models and automatic model builders. Through a novel logging method, the authors report gTPP usage for more than 200 Janssen drug discovery scientists. Conclusion: The investigators successfully enabled the rapid and systematic implementation of predictive ML tools across a drug discovery pipeline in all therapeutic areas. This experience provides useful guidance for other large-scale AI/ML deployment efforts.
Assuntos
Inibidores das Enzimas do Citocromo P-450/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Desenvolvimento de Medicamentos , Inibidores das Enzimas do Citocromo P-450/química , Humanos , Modelos MolecularesRESUMO
Drug discovery building blocks available commercially or within an internal inventory cover a diverse range of chemical space and yet describe only a tiny fraction of all chemically feasible reagents. Vendors will eagerly provide tools to search the former; there is no straightforward method of mining the latter. We describe a procedure and use case in assembling chemical structures not available for purchase but that could likely be synthesized in one robust chemical transformation starting from readily available building blocks. Accessing this vast virtual chemical space dramatically increases our curated collection of reagents available for medicinal chemistry exploration and novel hit generation, almost tripling the number of those with 10 or fewer atoms.
RESUMO
Acid-sensing ion channels (ASICs) are proton-gated cation channels critical for neuronal functions. Studies of ASIC1, a major ASIC isoform and proton sensor, have identified acidic pocket, an extracellular region enriched in acidic residues, as a key participant in channel gating. While binding to this region by the venom peptide psalmotoxin modulates channel gating, molecular and structural mechanisms of ASIC gating modulation by small molecules are poorly understood. Here, combining functional, crystallographic, computational and mutational approaches, we show that two structurally distinct small molecules potently and allosterically inhibit channel activation and desensitization by binding at the acidic pocket and stabilizing the closed state of rat/chicken ASIC1. Our work identifies a previously unidentified binding site, elucidates a molecular mechanism of small molecule modulation of ASIC gating, and demonstrates directly the structural basis of such modulation, providing mechanistic and structural insight into ASIC gating, modulation and therapeutic targeting.
Assuntos
Canais Iônicos Sensíveis a Ácido/efeitos dos fármacos , Ativação do Canal Iônico/efeitos dos fármacos , Moduladores de Transporte de Membrana/farmacologia , Canais Iônicos Sensíveis a Ácido/química , Canais Iônicos Sensíveis a Ácido/genética , Canais Iônicos Sensíveis a Ácido/metabolismo , Animais , Sítios de Ligação , Células CHO , Cricetulus , Cinética , Potenciais da Membrana , Moduladores de Transporte de Membrana/química , Mutação , Ligação Proteica , Conformação Proteica , Relação Estrutura-Atividade , TaquifilaxiaRESUMO
During efforts to improve the bioavailability of FMS kinase inhibitors 1 and 2, a series of saturated and aromatic 4-heterocycles of reduced basicity were prepared and evaluated in an attempt to also improve the cardiovascular safety profile over lead arylamide 1, which possessed ion channel activity. The resultant compounds retained excellent potency and exhibited diminished ion channel activity.
Assuntos
Amidas/farmacologia , Compostos Heterocíclicos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Amidas/síntese química , Amidas/química , Relação Dose-Resposta a Droga , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Modelos Moleculares , Estrutura Molecular , Oxirredução , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A tandem one-pot reaction featuring a cross-coupling followed by an intramolecular oxetane ring opening by mild nucleophiles is reported. The overall transformation comprises a carbon-carbon bond formation along with a carbon-heteroatom bond construction providing diverse multicyclic ring systems with a pendant hydroxymethyl handle for further elaboration. This approach constitutes a convergent method for rapid access to various scaffolds. Furthermore, a comparison of computed low-energy conformers is presented to rationalize instances in which cyclization was not observed.
RESUMO
The topic of gender equality within the United States workforce is receiving a great deal of attention. The field of chemistry is no exception and is increasingly focused on taking steps to achieve gender diversity within the chemistry workforce. Over the past several years, many computational chemistry groups within large pharmaceutical companies have realized growth in the number of women, and here we discuss the key factors that we believe have played a role in attracting and retaining the authors of this review as computational chemists in pharma. Furthermore, we combine our professional experiences in the context of how computational methodology and technology have evolved over the past decades and how that evolution has facilitated the inclusion of more women into the field. Our hope is to be a part of a solution and provide insight that will allow the chemistry workforce to continue to make steps forward in attaining gender diversity in the workplace.
Assuntos
Descoberta de Drogas/tendências , Indústria Farmacêutica/tendências , Identidade de Gênero , Sexismo/tendências , Recursos Humanos/tendências , Feminino , Humanos , Estados UnidosRESUMO
Artificial intelligence and machine learning have demonstrated their potential role in predictive chemistry and synthetic planning of small molecules; there are at least a few reports of companies employing in silico synthetic planning into their overall approach to accessing target molecules. A data-driven synthesis planning program is one component being developed and evaluated by the Machine Learning for Pharmaceutical Discovery and Synthesis (MLPDS) consortium, comprising MIT and 13 chemical and pharmaceutical company members. Together, we wrote this perspective to share how we think predictive models can be integrated into medicinal chemistry synthesis workflows, how they are currently used within MLPDS member companies, and the outlook for this field.
Assuntos
Técnicas de Química Sintética/métodos , Química Farmacêutica/métodos , Aprendizado de Máquina , Indústria Química/métodos , Descoberta de Drogas/métodos , Modelos Químicos , Pesquisa Farmacêutica/métodosRESUMO
A series of pyrimidinopyridones has been designed, synthesized and shown to be potent and selective inhibitors of the FMS tyrosine kinase. Introduction of an amide substituent at the 6-position of the pyridone core resulted in a significant potency increase. Compound 24 effectively inhibited in vivo LPS-induced TNF in mice greater than 80%.
Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Desenho de Fármacos , Inibidores de Proteínas Quinases/farmacologia , Piridonas/farmacologia , Pirimidinas/farmacologia , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/química , Animais , Anti-Inflamatórios/síntese química , Antineoplásicos/síntese química , Lipopolissacarídeos/toxicidade , Camundongos , Modelos Químicos , Inibidores de Proteínas Quinases/síntese química , Piridinas/química , Piridonas/síntese química , Pirimidinas/síntese química , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
A series of 3,4,6-substituted 2-quinolones has been synthesized and evaluated as inhibitors of the kinase domain of macrophage colony-stimulating factor-1 receptor (FMS). The fully optimized compound, 4-(4-ethyl-phenyl)-3-(2-methyl-3H-imidazol-4-yl)-2-quinolone-6-carbonitrile 21b, has an IC(50) of 2.5 nM in an in vitro assay and 5.0 nM in a bone marrow-derived macrophage cellular assay. Inhibition of FMS signaling in vivo was also demonstrated in a mouse pharmacodynamic model.
Assuntos
Macrófagos/efeitos dos fármacos , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Quinolonas/síntese química , Quinolonas/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Proliferação de Células/efeitos dos fármacos , Polarização de Fluorescência , Genes fos/genética , Fator Estimulador de Colônias de Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Estrutura Molecular , Quinolonas/farmacocinética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor de Fator Estimulador de Colônias de Macrófagos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Baço/metabolismo , Relação Estrutura-AtividadeRESUMO
Complement activation has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury, acute respiratory distress syndrome, and acute transplant rejection. Even though the complement cascade provides several protein targets for potential therapeutic intervention only two complement inhibitors have been approved so far for clinical use including anti-C5 antibodies for the treatment of paroxysmal nocturnal hemoglobinuria and purified C1-esterase inhibitor replacement therapy for the control of hereditary angioedema flares. In the present study, optimization of potency and physicochemical properties of a series of thiophene amidine-based C1s inhibitors with potential utility as intravenous agents for the inhibition of the classical pathway of complement is described.
Assuntos
Complemento C1s/antagonistas & inibidores , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacologia , Animais , Sítios de Ligação , Meia-Vida , Modelos Moleculares , Estrutura Molecular , Ratos , Relação Estrutura-AtividadeRESUMO
The optimization of the arylamide lead 2 resulted in identification of a highly potent series of 2,4-disubstituted arylamides. Compound 8 (FMS kinase IC(50)=0.0008 microM) served as a proof-of-concept candidate in a collagen-induced model of arthritis in mice.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Receptor de Fator Estimulador de Colônias de Macrófagos/antagonistas & inibidores , Animais , Artrite/induzido quimicamente , Artrite/tratamento farmacológico , Colágeno , Relação Dose-Resposta a Droga , Camundongos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , Fatores de TempoRESUMO
An anti-inflammatory 1,2,4-phenylenetriamine-containing series of FMS inhibitors with a potential to form reactive metabolites was transformed into a series with equivalent potency by incorporation of carbon-based replacement groups. Structure-based modeling provided the framework to efficiently effect this transformation and restore potencies to previous levels. This optimization removed a risk factor for potential idiosyncratic drug reactions.