RESUMO
Adverse outcome pathways have shown themselves to be useful ways of understanding and expressing knowledge about sequences of events that lead to adverse outcomes (AOs) such as toxicity. In this paper we use the building blocks of adverse outcome pathways-namely key events (KEs) and key event relationships-to construct networks which can be used to make predictions of the likelihood of AOs. The networks of KEs are augmented by data from and knowledge about assays as well as by structure activity relationship predictions linking chemical classes to the observation of KEs. These inputs are combined within a reasoning framework to produce an information-rich display of the relevant knowledge and data and predictions of AOs both in the abstract case and for individual chemicals. Illustrative examples are given for skin sensitization, reprotoxicity and non-genotoxic carcinogenicity.
RESUMO
There is a pressing need for non-animal methods to predict skin sensitisation potential and a number of in chemico and in vitro assays have been designed with this in mind. However, some compounds can fall outside the applicability domain of these in chemico/in vitro assays and may not be predicted accurately. Rule-based in silico models such as Derek Nexus are expert-derived from animal and/or human data and the mechanism-based alert domain can take a number of factors into account (e.g. abiotic/biotic activation). Therefore, Derek Nexus may be able to predict for compounds outside the applicability domain of in chemico/in vitro assays. To this end, an integrated testing strategy (ITS) decision tree using Derek Nexus and a maximum of two assays (from DPRA, KeratinoSens, LuSens, h-CLAT and U-SENS) was developed. Generally, the decision tree improved upon other ITS evaluated in this study with positive and negative predictivity calculated as 86% and 81%, respectively. Our results demonstrate that an ITS using an in silico model such as Derek Nexus with a maximum of two in chemico/in vitro assays can predict the sensitising potential of a number of chemicals, including those outside the applicability domain of existing non-animal assays.
Assuntos
Alternativas aos Testes com Animais , Simulação por Computador , Árvores de Decisões , Dermatite Alérgica de Contato/etiologia , Dermatite Irritante/etiologia , Irritantes/toxicidade , Testes de Irritação da Pele/métodos , Pele/efeitos dos fármacos , Animais , Bases de Dados Factuais , Humanos , Irritantes/química , Bases de Conhecimento , Reprodutibilidade dos Testes , Software , Relação Estrutura-Atividade , Fluxo de TrabalhoRESUMO
The identification and development of novel drugs requires a multidisciplinary team of individuals whose membership changes during the lifecycle of a project. Incomplete knowledge transfer across this team can be a barrier to effective decision-making and efficient drug discovery. We have deployed a new infrastructure supporting information storage and distribution within small teams using Microsoft's SharePoint server technology in conjunction with the desktop application OneNote. This delivers a user-friendly collaborative workspace that is fast, flexible and carries a low training burden. Demand from drug project teams for this 'solution' has now resulted in site-wide deployment to over 500 people across research.
Assuntos
Descoberta de Drogas/métodos , Armazenamento e Recuperação da Informação/métodos , Comunicação Interdisciplinar , Conhecimento , Tomada de Decisões Gerenciais , Humanos , SoftwareRESUMO
Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.
Assuntos
Fármacos Anti-HIV/síntese química , Butanos/síntese química , Antagonistas dos Receptores CCR5 , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , Piperidinas/síntese química , Animais , Fármacos Anti-HIV/uso terapêutico , Butanos/farmacocinética , Butanos/uso terapêutico , Células CACO-2 , Linhagem Celular , Cães , Humanos , Piperidinas/farmacocinética , Piperidinas/uso terapêutico , Ratos , Receptores CCR5/metabolismo , Estereoisomerismo , Triazóis/síntese químicaRESUMO
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR's which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential.
Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Antagonistas dos Receptores CCR5 , Piperidinas/síntese química , Piperidinas/farmacologia , Fármacos Anti-HIV/química , Técnicas de Química Combinatória , Desenho de Fármacos , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HIV-1/efeitos dos fármacos , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.
Assuntos
Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Butanos/síntese química , Butanos/farmacologia , Antagonistas dos Receptores CCR5 , Piperidinas/farmacologia , Síndrome da Imunodeficiência Adquirida/tratamento farmacológico , Fármacos Anti-HIV/química , Butanos/química , Técnicas de Química Combinatória , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Humanos , Estrutura Molecular , Relação Estrutura-Atividade , Tropanos/químicaRESUMO
Stereoselective nucleophilic epoxidation of protected 3-amino and 3-hydroxy-substituted 1-arylthio-1-nitroalkenes, followed by intramolecular capture involving the amino and hydroxyl protecting groups, has led to the formation of isomeric oxazolidinones 5 and 7, and a cyclic carbonate 11. Together with the oxazolidinone precursor anti-alpha-bromo thioester 15a, the absolute and relative stereochemistry of these compounds has been determined by X-ray crystallography.
Assuntos
Alcenos/química , Aminoácidos/síntese química , Compostos de Epóxi/química , Ésteres/síntese química , Oxazolidinonas/síntese química , Cristalografia por Raios X , EstereoisomerismoRESUMO
1-isoquinolinylguanidines were previously disclosed as potent and selective inhibitors of urokinase-type plasminogen activator (uPA). Further investigation of this template has revealed that incorporation of a 7-sulfonamide group furnishes a new series of potent and highly selective uPA inhibitors. Potency and selectivity can be achieved with sulfonamides derived from a variety of amines and is further enhanced by the incorporation of sulfonamides derived from amino acids. The binding mode of these 1-isoquinolinylguanidines has been investigated by X-ray cocrystallization studies. uPA inhibitor 26 was selected for further evaluation based on its excellent enzyme potency (Ki 10 nM) and selectivity profile (4000-fold versus tPA and 2700-fold versus plasmin). In vitro, compound 26 is able to inhibit exogenous uPA in human chronic wound fluid (IC50=0.89 microM). In vivo, in a porcine acute excisional wound model, following topical delivery, compound 26 is able to penetrate into pig wounds and inhibit exogenous uPA activity with no adverse effect on wound healing parameters. On the basis of this profile, compound 26 (UK-371,804) was selected as a candidate for further preclinical evaluation for the treatment of chronic dermal ulcers.
Assuntos
Antiulcerosos/síntese química , Guanidinas/síntese química , Quinolinas/síntese química , Sulfonamidas/síntese química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Doença Aguda , Animais , Antiulcerosos/química , Antiulcerosos/farmacologia , Sítios de Ligação , Doença Crônica , Cristalografia por Raios X , Guanidinas/química , Guanidinas/farmacologia , Humanos , Técnicas In Vitro , Modelos Moleculares , Ligação Proteica , Quinolinas/química , Quinolinas/farmacologia , Pele/lesões , Dermatopatias/enzimologia , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Suínos , Úlcera/enzimologia , Ativador de Plasminogênio Tipo Uroquinase/química , Cicatrização/efeitos dos fármacosRESUMO
Female sexual arousal disorder (FSAD) is a highly prevalent sexual disorder affecting up to 40% of women. We describe herein our efforts to identify a selective neutral endopeptidase (NEP) inhibitor as a potential treatment for FSAD. The rationale for this approach, together with a description of the medicinal chemistry strategy, lead compounds, and SAR investigations are detailed. In particular, the strategy of starting with the clinically precedented selective NEP inhibitor, Candoxatrilat, and targeting low molecular weight and relatively polar mono-carboxylic acids is described. This led ultimately to the prototype development candidate R-13, for which detailed pharmacology and pharmacokinetic parameters are presented.(1)
Assuntos
Ácidos Carbocíclicos/síntese química , Amidas/síntese química , Neprilisina/antagonistas & inibidores , Ácidos Pentanoicos/síntese química , Disfunções Sexuais Psicogênicas/tratamento farmacológico , Tiadiazóis/síntese química , Ácidos Carbocíclicos/farmacocinética , Ácidos Carbocíclicos/farmacologia , Amidas/farmacocinética , Amidas/farmacologia , Animais , Células CHO , Clitóris/irrigação sanguínea , Clitóris/efeitos dos fármacos , Cricetinae , Cricetulus , Cães , Feminino , Humanos , Masculino , Ácidos Pentanoicos/farmacocinética , Ácidos Pentanoicos/farmacologia , Piridinas/síntese química , Piridinas/farmacocinética , Piridinas/farmacologia , Coelhos , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Fluxo Sanguíneo Regional/efeitos dos fármacos , Especificidade da Espécie , Estereoisomerismo , Relação Estrutura-Atividade , Tiadiazóis/farmacocinética , Tiadiazóis/farmacologia , Vagina/irrigação sanguínea , Vagina/efeitos dos fármacosRESUMO
Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/antagonistas & inibidores , Azetidinas/síntese química , Pirimidinas/síntese química , Pirimidinonas/síntese química , 3',5'-GMP Cíclico Fosfodiesterases/química , Administração Oral , Animais , Azetidinas/química , Azetidinas/farmacologia , Disponibilidade Biológica , Células CACO-2 , Cristalografia por Raios X , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5 , Cães , Relação Dose-Resposta a Droga , Disfunção Erétil/tratamento farmacológico , Humanos , Cetonas/química , Masculino , Modelos Moleculares , Estrutura Molecular , Pirimidinas/química , Pirimidinas/farmacologia , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-AtividadeRESUMO
A series of 1-isoquinolinylguanidines are shown to be potent inhibitors of uPA with selectivity over tPA and plasmin. Potency is enhanced by the presence of a 4-halo and a 7-aryl substituent, particularly when substituted by a 3-carboxylic acid group. Compound 13j (UK-356,202) combines excellent potency and selectivity, and has been selected as a candidate for clinical evaluation.
Assuntos
Guanidinas/química , Isoquinolinas/química , Inibidores de Serina Proteinase/química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Guanidinas/farmacologia , Humanos , Isoquinolinas/farmacologia , Valor Preditivo dos Testes , Inibidores de Serina Proteinase/farmacologia , Ativador de Plasminogênio Tipo Uroquinase/metabolismoRESUMO
The identification of 2-pyridinylguanidines (e.g., 27 and 28) as selective inhibitors of urokinase-type plasminogen activator (uPA) is described. The X-ray crystal structure of 27 has been determined, and modelling has been used to predict binding in the enzyme active site.
Assuntos
Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Piridinas/química , Ativador de Plasminogênio Tipo Uroquinase/antagonistas & inibidores , Inibidores Enzimáticos/química , Guanidinas/química , Modelos Moleculares , Difração de Raios XRESUMO
Based on previous modeling predictions, a series of (3-substituted-5-chloro-2-pyridinyl)guanidines have been designed with good potency and selectivity for urokinase-type plasminogen activator (uPA). Compound 36 has a K(i) of 0.17 microM and greater than 300-fold selectivity with respect to tPA and plasmin.