RESUMO
Successful structure-based drug design (SBDD) requires the optimization of interactions with the target protein and the minimization of ligand strain. Both factors are often modulated by small changes in the chemical structure which can lead to profound changes in the preferred conformation and interaction preferences of the ligand. We draw from examples of a Roche project targeting phosphodiesterase 10 to highlight that details matter in SBDD. Data mining in crystal structure databases can help to identify these sometimes subtle effects, but it is also a great resource to learn about molecular recognition in general and can be used as part of molecular design tools. We illustrate the use of the Cambridge Structural Database for identifying preferred structural motifs for intramolecular hydrogen bonding and of the Protein Data Bank for deriving propensities for protein-ligand interactions.
Assuntos
Mineração de Dados , Desenho de Fármacos , Ligantes , Bases de Dados Factuais , AprendizagemRESUMO
Pyrido pyrimidinones are selective agonists of the human high affinity niacin receptor GPR109A (HM74A). They show no activity on the highly homologous low affinity receptor GPR109B (HM74). Starting from a high throughput screening hit the in vitro activity of the pyrido pyrimidinones was significantly improved providing lead compounds suitable for further optimization.
Assuntos
Niacina/metabolismo , Pirimidinonas/química , Pirimidinonas/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Microssomos Hepáticos/metabolismo , Pirimidinonas/administração & dosagem , Pirimidinonas/metabolismo , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
During a program directed at selective NK(1) receptor antagonists, we serendipitously discovered an NK(1) receptor ligand with additional affinity for the NK(3) receptor. Recognising an opportunity for a drug discovery program aiming for dual NK(1)/NK(3) receptor antagonists, we prepared a series of analogues from a novel, versatile building block. From this series emerged compounds with high and balanced affinities for the NK(1) and the NK(3) receptors. Typical representatives of this series were active in the gerbil foot tapping assay after oral administration.
Assuntos
Antagonistas dos Receptores de Neurocinina-1 , Receptores da Neurocinina-3/antagonistas & inibidores , Administração Oral , Animais , Descoberta de Drogas , Ligantes , Modelos Moleculares , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismoRESUMO
BACKGROUND: Several factors contribute to the development failure of novel pharmaceuticals, one of the most important being adverse effects in pre-clinical and clinical studies. Early identification of off-target compound activity can reduce safety-related attrition in development. In vitro profiling of drug candidates against a broad range of targets is an important part of the compound selection process. Many compounds are synthesized during early drug discovery, making it necessary to assess poly-pharmacology at a limited number of targets. This paper describes how a rational, statistical-ranking approach was used to generate a cost-effective, optimized panel of assays that allows selectivity focused structure-activity relationships to be explored for many molecules. This panel of 50 targets has been used to routinely screen Roche small molecules generated across a diverse range of therapeutic targets. Target hit rates from the Bioprint® database and internal Roche compounds are discussed. We further describe an example of how this panel was used within an anti-infective project to reduce in vivo testing. METHOD: To select the optimized panel of targets, IC50 values of compounds in the BioPrint® database were used to identify assay "hits" i.e. IC50â¯≤â¯1⯵M in 123 different in vitro pharmacological assays. If groups of compounds hit the same targets, the target with the higher hit rate was selected, while others were considered redundant. Using a step-wise analysis, an assay panel was identified to maximize diversity and minimize redundancy. Over a five-year period, this panel of 50 off-targets was used to screen ≈1200 compounds synthesized for Roche drug discovery programs. Compounds were initially tested at 10⯵M and hit rates generated are reported. Within one project, the number of hits was used to refine the choice of compounds being assessed in vivo. RESULTS: 95% of compounds from the BioPrint® panel were identified within the top 47-ranked assays. Based on this analytical approach and the addition of three targets with established safety concerns, a Roche panel was created for external screening. hERG is screened internally and not included in this analysis. Screening at 10⯵M in the Roche panel identified that adenosine A3 and 5HT2B receptors had the highest hit rates (~30%), with 50% of the targets having a hit rate of ≤4%. An anti-infective program identified that a high number of hits in the Roche panel was associated with mortality in 19 mouse tolerability studies. To reduce the severity and number of such studies, future compound selections integrated the panel hit score into the selection process for in vivo studies. It was identified that compounds which hit less targets in the panel and had free plasma exposures of ~2⯵M were generally better tolerated. DISCUSSION: This paper describes how an optimized panel of 50 assays was selected on the basis of hit similarity at 123 targets. This reduced panel, provides a cost-effective screening panel for assessing compound promiscuity, whilst also including many safety-relevant targets. Frequent use of the panel in early drug discovery has provided promiscuity and safety-relevant information to inform pre-clinical drug development at Roche.
RESUMO
The optimisation of molecular properties within a series of 2-amino dihydroquinazoline 5-HT5A/5-HT7 receptor ligands resulted in a significantly improved brain-to-plasma ratio, enhancing the pharmacological utility of these compounds. By modulating the lipophilicity and pKa, a 20-fold increase in brain-to-plasma ratio could be achieved, leading to micromolar brain concentrations after oral administration. The enantiomers of one representative of this series of improved compounds were separated, and the configuration of the eutomer was determined by X-ray crystallography.
Assuntos
Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Guanidinas/farmacocinética , Receptores de Serotonina/metabolismo , Animais , Guanidinas/química , Guanidinas/farmacologia , Humanos , Cinética , Ligantes , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Ratos , Receptores de Serotonina/química , Relação Estrutura-AtividadeRESUMO
The optimisation of affinity and selectivity in a novel series of dual 5-HT5A/5-HT7 receptor ligands is described. Brain penetrant 2-aminodihydroquinazolines with low nanomolar affinities were identified.
Assuntos
Guanidinas/metabolismo , Quinazolinas/metabolismo , Receptores de Serotonina/metabolismo , Encéfalo/metabolismo , Guanidinas/química , Guanidinas/farmacocinética , Guanidinas/farmacologia , Humanos , Cinética , Ligantes , Pirimidinas/química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Quinazolinas/química , Quinazolinas/farmacocinética , Quinazolinas/farmacologia , Receptores de Serotonina/química , Relação Estrutura-AtividadeRESUMO
Fragment screening revealed that tyramine binds to the active site of the Alzheimer's disease drug target BACE-1. Hit expansion by selection of compounds from the Roche compound library identified tyramine derivatives with improved binding affinities as monitored by surface plasmon resonance. X-ray structures show that the amine of the tyramine fragment hydrogen-bonds to the catalytic water molecule. Structure-guided ligand design led to the synthesis of further low molecular weight compounds that are starting points for chemical leads.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Fragmentos de Peptídeos/metabolismo , Tiramina/metabolismo , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/química , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Ácido Aspártico Endopeptidases/química , Sítios de Ligação , Cristalografia por Raios X , Humanos , Cinética , Modelos Moleculares , Fragmentos de Peptídeos/química , Ligação Proteica , Conformação Proteica , Tiramina/químicaRESUMO
Prevalence of type 2 diabetes has increased dramatically in the last decades. Current medicines are not yet capable to efficiently prevent or reverse progression of the disease and its associated comorbidities. As a consequence, there is a great need for novel antidiabetic drugs. Treatments of type 2 diabetes that are based on enhanced and sustained action of insulinotropic incretin hormones such as GLP-1 have received much attention in the past years. Treatment strategies include administration of: 1) GLP-1 analogues that are resistant to degradation by the serine protease DPP-IV, and 2) small molecule DPP-IV inhibitors that are able to provide sustained action of endogenous GLP-1, again by preventing its degradation. This review summarizes recent research results for the second approach. It briefly touches upon the advantages that treatment of type 2 diabetes with DPP-IV inhibitors may offer over current medications. In the main section, several important structural classes of DPP-IV inhibitors are described and compared based on literature data. Specific attention is given to the analysis of several X-ray structures of enzyme-inhibitor co-crystals. Finally, as clinical data are steadily emerging for some of the most advanced development candidates, the last section of this review is providing a brief overview of some efficacy data from recent clinical studies with DPP-IV inhibitors.
Assuntos
Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Mimetismo Molecular , Estrutura Molecular , Inibidores de Proteases/química , Difração de Raios XRESUMO
Negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGlu5) have potential for the treatment of psychiatric diseases including depression, fragile X syndrome (FXS), anxiety, obsessive-compulsive disorders, and levodopa induced dyskinesia in Parkinson's disease. Herein we report the optimization of a weakly active screening hit 1 to the potent and selective compounds chloro-4-[1-(4-fluorophenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]pyridine (basimglurant, 2) and 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1H-imidazol-4-yl)ethynyl)pyridine (CTEP, 3). Compound 2 is active in a broad range of anxiety tests reaching the same efficacy but at a 10- to 100-fold lower dose compared to diazepam and is characterized by favorable DMPK properties in rat and monkey as well as an excellent preclinical safety profile and is currently in phase II clinical studies for the treatment of depression and fragile X syndrome. Analogue 3 is the first reported mGlu5 NAM with a long half-life in rodents and is therefore an ideal tool compound for chronic studies in mice and rats.
Assuntos
Depressão/tratamento farmacológico , Descoberta de Drogas , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Imidazóis/farmacologia , Piridinas/farmacologia , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Humanos , Imidazóis/síntese química , Imidazóis/química , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The alpha-effect can be used in the acceleration of the Diels-Alder reaction between a series of dienes and electron deficient dienophiles using iminium ion catalysis, providing a novel molecular scaffold capable of performing this class of catalytic process.
RESUMO
Polypharmacology describes the activity of compounds at multiple targets. Current research focuses on two aspects of polypharmacology: (1) unintended polypharmacology can lead to adverse effects; (2) polypharmacology across several disease-relevant targets can improve therapeutic efficacy, prevent drug resistance, or reduce therapeutic-target-related adverse effects. This perspective reviews these interconnected aspects of polypharmacology. The first part discusses the relevance of polypharmacology for the safety of drugs, the mitigation of safety risks, and methods to identify polypharmacological compounds early in the drug discovery process. The second part discusses the advantages of polypharmacology in the treatment of multigenic diseases and infections, and opportunities for drug discovery and drug repurposing. This perspective aims to provide a balanced view on polypharmacology, which can compromise the safety of drugs, but can also confer superior efficacy.
Assuntos
Polifarmacologia , Segurança , Animais , Doenças Transmissíveis/tratamento farmacológico , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , HumanosRESUMO
The term 'pharmacological promiscuity' describes the activity of a single compound against multiple targets. When undesired, promiscuity is a major safety concern that needs to be detected as early as possible in the drug discovery process. The analysis of large datasets reveals that the majority of promiscuous compounds are characterized by recognizable molecular properties and structural motifs, the most important one being a basic center with a pK(a)(B)>6. These compounds interact with a small set of targets such as aminergic GPCRs; some of these targets attract surprisingly high hit rates. In this review, we discuss current trends in the assessment of pharmacological promiscuity and propose strategies to enable early detection and mitigation.
Assuntos
Descoberta de Drogas/métodos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Preparações Farmacêuticas/química , Animais , Humanos , Farmacologia , Relação Estrutura-AtividadeRESUMO
The term "pharmacological promiscuity" describes a compound's pharmacological activity at multiple targets. Pharmacological promiscuity is undesired in typical drug discovery projects, which focus on the "one drug-one target" paradigm. Off-target activity can lead to adverse drug reactions, or can obscure pharmacodynamic effects in animal models. Therefore, advanced lead compounds, pharmacological tool compounds, and drug candidates are usually screened against panels of safety-relevant targets to detect unwanted pharmacological activities. To identify determinants of pharmacological promiscuity, we compared the panel screening outcomes of 213 recent Roche compounds with their molecular properties. Pronounced promiscuity was not observed below a threshold Clog P value of 2. For basic compounds, the propensity for weak off-target activity was found to increase with calculated basicities, whereas the potential for strong off-target activity depends more qualitatively on the presence of a positive charge at physiological pH. Compounds originating from projects with an aminergic receptor or transporter as a therapeutic target are particularly prone to promiscuity; the promiscuity of such compounds is mainly caused by their activity at other aminergic targets in the screening panel.
Assuntos
Indústria Farmacêutica , Preparações Farmacêuticas/química , Descoberta de Drogas , Interações Hidrofóbicas e Hidrofílicas , Íons/química , Lipídeos/química , Solubilidade , Especificidade por SubstratoRESUMO
Detailed information on the metabolic fate of lead compounds can be a powerful tool for an informed approach to the stabilization of metabolically labile compounds in the lead optimization phase. The combination of high performance liquid chromatography (HPLC) with nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) has been used to give comprehensive structural data on metabolites of novel drugs in development. Recently, increased automation and the embedding of on-line solid-phase extraction (SPE) into a integrated LC-SPE-NMR-MS system have improved enormously the detection limits of this approach. The new technology platform allows the analysis of complex mixtures from microsome incubations, combining low material requirements with relatively high throughput. Such characteristics make it possible to thoroughly characterize metabolites of selected compounds at earlier phases along the path to lead identification and clinical candidate selection, thus providing outstanding guidance in the process of eliminating undesired metabolism and detecting active or potentially toxic metabolites. Such an approach was applied at the lead identification stage of a backup program on metabotropic glutamate receptor 5 (mGlu5) allosteric inhibition. The major metabolites of a lead 5-aminothiazole-4-carboxylic acid amide 1 were synthesized and screened, revealing significant in vitro activity and possible involvement in the overall pharmacodynamic behavior of 1. The information collected on the metabolism of the highly active compound 1 was pivotal to the synthesis of related compounds with improved microsomal stability.
Assuntos
Aminopiridinas/metabolismo , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tiazóis/metabolismo , Regulação Alostérica , Aminopiridinas/síntese química , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Microssomos Hepáticos/química , Oxirredução , Preparações Farmacêuticas/síntese química , Receptor de Glutamato Metabotrópico 5 , Extração em Fase Sólida/métodos , Estereoisomerismo , Tiazóis/síntese químicaRESUMO
Cyanopyrrolidines (cyanopyrrolidides, pyrrolidine-2-nitriles, prolinenitriles) as inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV, DP IV, CD26, EC 3.4.14.5) were first reported in 1995. The interest in this compound class grew immensely when DPP-IV was discovered as a target for the treatment of type 2 diabetes. The research on cyanopyrrolidines cumulated in the discoveries of vildagliptin (LAF237, NVP-LAF237) and saxagliptin (BMS-477118). These compounds entered Phase III clinical trials in 2004 and 2005, respectively, and an application for market approval has been filed for vildagliptin in 2006. Today cyanopyrrolidines are, as judged by the numbers of patent applications, the most prominent of several series of DPP-IV inhibitors, and have the potential to become valuable medicines for type 2 diabetes in the near future. This review summarizes some historical aspects of the discovery of cyanopyrrolidine DPP-IV inhibitors, and then focuses mainly on structure-activity-relationships, the evolution of different subseries, the possibilities to improve on the chemical instability that is associated with this compound class, and on the discoveries of vildagliptin and saxagliptin. Within this context, the properties of individual compounds and results from biological studies are discussed. The rationale of DPP-IV inhibition, clinical data, and the relevance of selectivity over related proteases are extensively reviewed in other contributions to this issue of Curr. Top. Med. Chem., and are therefore only very briefly touched.
Assuntos
Inibidores da Dipeptidil Peptidase IV , Pirrolidinas/farmacologia , Inibidores de Serina Proteinase/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Pirrolidinas/química , Pirrolidinas/uso terapêutico , Inibidores de Serina Proteinase/química , Inibidores de Serina Proteinase/uso terapêutico , Relação Estrutura-AtividadeRESUMO
Structural modifications of the gamma-secretase inhibitor, LY411575, led to a malonamide analogue (S),(S)-1 with potent inhibitory activity in vitro, but disappointing activity in a mouse model of Alzheimer's disease. Identification and replacement of a metabolically labile position provided an improved compound (R/S),(S)-13 with high in vitro activity (IC(50)=1.7 nM), and in vivo activity after oral administration (MED=3 mg/kg). Further modifications gave an equipotent carbamate analogue 14 with improved molecular properties.
Assuntos
Alanina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Administração Oral , Alanina/química , Alanina/farmacologia , Animais , Azepinas/administração & dosagem , Azepinas/química , Cromatografia Líquida de Alta Pressão , Camundongos , Camundongos Transgênicos , Espectrometria de Massas em TandemRESUMO
A novel class of potent and stable mGlu5 receptor antagonists was developed by combining information from a high-throughput screening campaign with the structure of the known anxiolytic fenobam. Representative compounds from this class show favorable pharmacokinetic properties and are active in an in vivo model of anxiety.
Assuntos
Ansiolíticos/síntese química , Benzoxazóis/síntese química , Benzoxazóis/farmacocinética , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/farmacocinética , Ansiedade/tratamento farmacológico , Benzoxazóis/administração & dosagem , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Imidazóis/química , Modelos Animais , Farmacocinética , Ligação Proteica , Ratos , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
In a search for novel DPP-IV inhibitors, 2-aminobenzo[a]quinolizines were identified as submicromolar HTS hits. Due to the difficult synthetic access to this compound class, 1,3-disubstituted 4-aminopiperidines were used as model compounds for optimization. The developed synthetic methodology and the SAR could be transferred to the 2-aminobenzo[a]quinolizine series, leading to highly active DPP-IV inhibitors.
Assuntos
Inibidores de Adenosina Desaminase , Inibidores da Dipeptidil Peptidase IV , Glicoproteínas/antagonistas & inibidores , Piperidinas/química , Inibidores de Proteases/química , Adenosina Desaminase/química , Dipeptidil Peptidase 4/química , Glicoproteínas/química , Humanos , Piperidinas/síntese química , Piperidinas/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
Optimization of affinity and microsomal stability led to identification of the potent, metabolically stable fenobam analog 4l. Robust in vivo efficacy of 4l was demonstrated in four different models of anxiety. Additionally, a ligand based pharmacophore alignment of fenobam and MPEP is proposed.
Assuntos
Imidazóis/química , Imidazóis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Animais , Ansiolíticos/síntese química , Desenho de Fármacos , Humanos , Ligantes , Piridinas/química , Receptor de Glutamato Metabotrópico 5 , Relação Estrutura-AtividadeRESUMO
Optimisation of affinity, chemical stability, metabolic stability and solubility led from a chemically labile HTS hit 1 to mGlu5 receptor antagonists (24-26) with high affinity for the allosteric MPEP binding site, improved microsomal metabolic stability and anxiolytic-like activity in vivo as assessed by the Vogel conflict drinking test.