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1.
J Med Chem ; 63(20): 11964-11971, 2020 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-32955254

RESUMO

Machine learning approaches promise to accelerate and improve success rates in medicinal chemistry programs by more effectively leveraging available data to guide a molecular design. A key step of an automated computational design algorithm is molecule generation, where the machine is required to design high-quality, drug-like molecules within the appropriate chemical space. Many algorithms have been proposed for molecular generation; however, a challenge is how to assess the validity of the resulting molecules. Here, we report three Turing-inspired tests designed to evaluate the performance of molecular generators. Profound differences were observed between the performance of molecule generators in these tests, highlighting the importance of selection of the appropriate design algorithms for specific circumstances. One molecule generator, based on match molecular pairs, performed excellently against all tests and thus provides a valuable component for machine-driven medicinal chemistry design workflows.


Assuntos
Algoritmos , Aprendizado de Máquina , Química Farmacêutica , Desenho de Fármacos , Humanos , Estrutura Molecular
2.
J Med Chem ; 63(2): 714-746, 2020 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-31904959

RESUMO

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize N-acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an N-methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.


Assuntos
Ensaios de Triagem em Larga Escala/métodos , Proteínas/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Benzimidazóis/química , Benzimidazóis/farmacocinética , Benzimidazóis/farmacologia , Quimiocina CCL2/biossíntese , Cristalografia por Raios X , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Humanos , Interleucina-6/antagonistas & inibidores , Leucócitos/efeitos dos fármacos , Masculino , Camundongos , Modelos Moleculares , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas
7.
Org Biomol Chem ; 14(1): 172-82, 2016 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-26468867

RESUMO

The isomers of dibenzylamino-1-methylcyclohexan-1-ol and dibenzylamino-1-trifluoromethylcyclohexan-1-ol have been prepared. The stereochemistry of these compounds was unequivocally assigned through a combination of NMR spectroscopy and single crystal X-ray analysis. The cis-isomer of 3-N,N-dibenzylamino-1-trifluoromethylcyclohexanol and its derivatives display an unusual conformational behaviour in both solution-phase and the solid-state, where the amino group usually adopts an axial conformation.


Assuntos
Benzilaminas/síntese química , Cicloexanóis/síntese química , Benzilaminas/química , Cristalografia por Raios X , Cicloexanóis/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Conformação Molecular , Estereoisomerismo
8.
J Med Chem ; 58(18): 7381-99, 2015 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-26301626

RESUMO

Optimization of lead compound 1, through extensive use of structure-based design and a focus on PI3Kδ potency, isoform selectivity, and inhaled PK properties, led to the discovery of clinical candidates 2 (GSK2269557) and 3 (GSK2292767) for the treatment of respiratory indications via inhalation. Compounds 2 and 3 are both highly selective for PI3Kδ over the closely related isoforms and are active in a disease relevant brown Norway rat acute OVA model of Th2-driven lung inflammation.


Assuntos
Indazóis/química , Oxazóis/química , Inibidores de Fosfoinositídeo-3 Quinase , Doenças Respiratórias/tratamento farmacológico , Sulfonamidas/química , Administração por Inalação , Animais , Asma/tratamento farmacológico , Feminino , Humanos , Indazóis/farmacocinética , Indazóis/farmacologia , Indóis , Isoenzimas/antagonistas & inibidores , Masculino , Microssomos/metabolismo , Simulação de Acoplamento Molecular , Ovalbumina/imunologia , Oxazóis/farmacocinética , Oxazóis/farmacologia , Piperazinas , Pneumonia/tratamento farmacológico , Pneumonia/imunologia , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Células Th2/imunologia
9.
Drug Discov Today ; 18(23-24): 1158-72, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24051399

RESUMO

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.


Assuntos
Química Farmacêutica/educação , Desenho de Fármacos , Descoberta de Drogas/métodos , Currículo , Indústria Farmacêutica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Inibidores de Fosfoinositídeo-3 Quinase , Solubilidade
10.
J Med Chem ; 56(11): 4729-37, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23656296

RESUMO

REV-ERBα has emerged as an important target for regulation of circadian rhythm and its associated physiology. Herein, we report on the optimization of a series of REV-ERBα agonists based on GSK4112 (1) for potency, selectivity, and bioavailability. (1) Potent REV-ERBα agonists 4, 10, 16, and 23 are detailed for their ability to suppress BMAL and IL-6 expression from human cells while also demonstrating excellent selectivity over LXRα. Amine 4 demonstrated in vivo bioavailability after either iv or oral dosing.


Assuntos
Aminas/síntese química , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/agonistas , Aminas/química , Aminas/farmacologia , Animais , Disponibilidade Biológica , Proteínas de Transporte/metabolismo , Linhagem Celular , Ritmo Circadiano , Glicina/análogos & derivados , Glicina/síntese química , Glicina/química , Glicina/farmacologia , Humanos , Receptores X do Fígado , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos/metabolismo , Fragmentos de Peptídeos/metabolismo , Proteínas de Ligação a RNA , Ensaio Radioligante , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química , Tiofenos/farmacologia
11.
ACS Comb Sci ; 13(3): 280-5, 2011 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-21438502

RESUMO

Triphenylphosphine tagged with a short poly-(ethyleneglycol)-ω-monomethyl ether chain (light MPEG, 10−16 ethylenoxy units, (M)TPP-G2) and an MPEG-tagged version of diethyl azodicarboxylate ((M)DEAD) have been used to prepare a 20 member library of esters, ethers, and sulfonamides, with cLogP's in the range of 1.4−5.7 on a 0.1 mmol scale. Removal of MPEG-tagged side products was achieved by MPEG-assisted solid-phase extraction (MSPE) on prepacked silica columns to give the products in good yield and high purity.


Assuntos
Técnicas de Química Combinatória , Peso Molecular , Extração em Fase Sólida
12.
J Chem Inf Model ; 50(10): 1872-86, 2010 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-20873842

RESUMO

Previous studies of the analysis of molecular matched pairs (MMPs) have often assumed that the effect of a substructural transformation on a molecular property is independent of the context (i.e., the local structural environment in which that transformation occurs). Experiments with large sets of hERG, solubility, and lipophilicity data demonstrate that the inclusion of contextual information can enhance the predictive power of MMP analyses, with significant trends (both positive and negative) being identified that are not apparent when using conventional, context-independent approaches.


Assuntos
Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Algoritmos , Bases de Dados Factuais , Canais de Potássio Éter-A-Go-Go/química , Humanos , Ligantes , Lipídeos/química , Estrutura Molecular , Solubilidade
13.
J Chem Inf Model ; 49(2): 195-208, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19434823

RESUMO

Neighborhood behavior describes the extent to which small structural changes defined by a molecular descriptor are likely to lead to small property changes. This study evaluates two methods for the quantification of neighborhood behavior: the optimal diagonal method of Patterson et al. and the optimality criterion method of Horvath and Jeandenans. The methods are evaluated using twelve different types of fingerprint (both 2D and 3D) with screening data derived from several lead optimization projects at GlaxoSmithKline. The principal focus of the work is the design of chemical arrays during lead optimization, and the study hence considers not only biological activity but also important drug properties such as metabolic stability, permeability, and lipophilicity. Evidence is provided to suggest that the optimality criterion method may provide a better quantitative description of neighborhood behavior than the optimal diagonal method.


Assuntos
Desenho de Fármacos , Permeabilidade
14.
Bioorg Med Chem Lett ; 19(5): 1380-5, 2009 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-19195882

RESUMO

Crystallography-driven optimisation of a lead derived from similarity searching of the GSK compound collection resulted in the discovery of a series of quinoline derivatives that were highly potent and selective inhibitors of PDE4 with a good pharmacokinetic profile in the rat. Quinolines 43 and 48 have potential as oral medicines for the treatment of COPD.


Assuntos
Inibidores da Fosfodiesterase 4 , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Quinolinas/administração & dosagem , Quinolinas/química , Administração Oral , Animais , Bovinos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Humanos , Masculino , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
15.
Bioorg Med Chem Lett ; 18(14): 4237-41, 2008 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-18539455

RESUMO

Optimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing.


Assuntos
Química Farmacêutica/métodos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/química , Inibidores da Fosfodiesterase 4 , Pirazóis/síntese química , Pirazóis/farmacocinética , Piridinas/síntese química , Piridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Benzamidas/farmacologia , Cristalografia por Raios X/métodos , Ciclopropanos/farmacologia , Desenho de Fármacos , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Modelos Biológicos , Modelos Químicos , Pirrolidinonas/química , Ratos , Rolipram/farmacologia , Fator de Necrose Tumoral alfa/metabolismo
16.
Bioorg Med Chem Lett ; 17(15): 4363-8, 2007 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-17600705

RESUMO

2,4-Dianilino pyrimidines are well-known inhibitors of tyrosine kinases including lymphocyte specific kinase (Lck). Structure-activity relationships at the 4-position are discussed and rationalised. Examples bearing a 2-methyl-5-hydroxyaniline substituent at the 4-position were especially potent but showed poor oral pharmacokinetics. Replacement of this substituent by 4-amino(5-methyl-1H-indazole) yielded compounds with comparable enzyme potency and improved pharmacokinetic properties.


Assuntos
Inibidores Enzimáticos/farmacologia , Indazóis/farmacologia , Proteína Tirosina Quinase p56(lck) Linfócito-Específica/antagonistas & inibidores , Inibidores Enzimáticos/farmacocinética , Indazóis/farmacocinética , Modelos Moleculares
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