Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 16 de 16
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
J Chem Inf Model ; 60(10): 4730-4749, 2020 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-32786699

RESUMO

The efflux transporter P-glycoprotein (P-gp) is responsible for the extrusion of a wide variety of molecules, including drug molecules, from the cell. Therefore, P-gp-mediated efflux transport limits the bioavailability of drugs. To identify potential P-gp substrates early in the drug discovery process, in silico models have been developed based on structural and physicochemical descriptors. In this study, we investigate the use of molecular dynamics fingerprints (MDFPs) as an orthogonal descriptor for the training of machine learning (ML) models to classify small molecules into substrates and nonsubstrates of P-gp. MDFPs encode the information from short MD simulations of the molecules in different environments (water, membrane, or protein pocket). The performance of the MDFPs, evaluated on both an in-house dataset (3930 compounds) and a public dataset from ChEMBL (1114 compounds), is compared to that of commonly used 2D molecular descriptors, including structure-based and property-based descriptors. We find that all tested classifiers interpolate well, achieving high accuracy on chemically diverse subsets. However, by challenging the models with external validation and prospective analysis, we show that only tree-based ML models trained on MDFPs or property-based descriptors generalize well to regions of the chemical space not covered by the training set.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP , Simulação de Dinâmica Molecular , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Aprendizado de Máquina , Estudos Prospectivos
2.
Chemistry ; 24(68): 17936-17947, 2018 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-30451324

RESUMO

Late-stage functionalization of lead compounds is of high interest in drug discovery since it offers an easy access to metabolites and derivatives of a lead compound without the need to redesign an often long multistep synthesis. Owing to their high degree of chemoselectivity, biocatalytic transformations, enzymatic oxidations in particular, are potentially very powerful because they could allow the synthesis of less lipophilic derivatives of a lead compound. In the majority of cases, enzymatic oxidations have been used in an empirical way as their regioselectivity is difficult to predict. In this publication, the concept of using docking/protecting groups in a biomimetic fashion was investigated, which could help steer the regioselectivity of a P450BM3 -mediated oxidation. A novel set of docking/protecting groups was designed that can be cleaved under very mild conditions and address the often problematic aqueous solubility of the substrates. Vabicaserin was used as tool compound containing typical groups such as basic, aliphatic, and aromatic moieties. The results were rationalized with the help of in silico docking and molecular dynamic studies.

3.
J Med Chem ; 61(17): 7503-7524, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-30080045

RESUMO

The glycine transporter 1 (GlyT1) has emerged as a key novel target for the treatment of schizophrenia. Herein, we report the synthesis and biological evaluation of aminotetralines and aminochromanes as novel classes of competitive GlyT1 inhibitors. Starting from a high-throughput screening hit, structure-activity relationship studies led first to the discovery of aminotetralines displaying high GlyT1 potency and selectivity, with favorable pharmacokinetic properties. Systematic investigations of various parameters (e.g., topological polar surface area, number of hydrogen bond donors) guided by ex vivo target occupancy evaluation resulted in lead compounds possessing favorable brain penetration properties as for (7 S,8 R)-27a. Further optimization revealed compounds with reduced efflux liabilities as for aminochromane 51b. In an in vivo efficacy model (7 S,8 R)-27a, dose-dependently reversed L-687,414 induced hyperlocomotion in mice with an ED50 of 0.8 mg/kg. All these results suggest (7 S,8 R)-27a and 51b as new GlyT1 inhibitors worthy of further profiling.


Assuntos
Encéfalo/efeitos dos fármacos , Cromanos/química , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Tetra-Hidronaftalenos/química , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Ligação Competitiva , Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Feminino , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Ensaios de Triagem em Larga Escala/métodos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirrolidinonas/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xenopus
4.
J Med Chem ; 61(17): 7486-7502, 2018 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-29969029

RESUMO

The development of glycine transporter 1 (GlyT1) inhibitors may offer putative treatments for schizophrenia and other disorders associated with hypofunction of the glutaminergic N-methyl-d-aspartate (NMDA) receptor. Herein, we describe the synthesis and biological evaluation of a series of 3,4-disubstituted pyrrolidine sulfonamides as competitive GlyT1 inhibitors that arose from de novo scaffold design. Relationship of chemical structure to drug-drug interaction (DDI) and bioactivation was mechanistically investigated. Murine studies were strategically incorporated into the screening funnel to provide early assessments of in vivo target occupancy (TO) by ex vivo binding studies. Advanced compounds derived from iterative structure-activity relationship (SAR) studies possessed high potency in ex vivo binding studies and good brain penetration, promising preliminary in vivo efficacy, acceptable preclinical pharmacokinetics, and manageable DDI and bioactivation liabilities.


Assuntos
Encéfalo/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Pirrolidinas/química , Sulfonamidas/química , Animais , Encéfalo/metabolismo , Técnicas de Química Sintética , Cães , Relação Dose-Resposta a Droga , Desenho de Fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Humanos , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos , Microssomos Hepáticos/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Oócitos/efeitos dos fármacos , Oócitos/metabolismo , Pirrolidinonas/efeitos adversos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Xenopus
5.
Bioorg Med Chem Lett ; 23(20): 5471-83, 2013 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-23992859

RESUMO

Multiple technologies have emerged for structural diversification and efficient production of metabolites of drug molecules. These include expanded use of enzymatic and bioorganic transformations that mimic biological systems, biomimetic catalysis and electrochemical techniques. As this field continues to mature the breadth of transformations is growing beyond simple oxidative processes due in part to parallel development of more efficient catalytic methods for functionalization of unactivated scaffolds. These technologies allow for efficient structural diversification of both aromatic and aliphatic substrates in many cases via single step reactions without the use of protecting groups.


Assuntos
Materiais Biomiméticos/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Materiais Biomiméticos/química , Catálise , Sistema Enzimático do Citocromo P-450/genética , Técnicas Eletroquímicas , Humanos , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/genética , Estereoisomerismo
6.
Bioorg Med Chem Lett ; 16(10): 2641-7, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16517159

RESUMO

The synthesis and SAR of novel nanomolar thrombin inhibitors with the common backbone HOOC-CH(2)-d-cyclohexylalanyl-3,4-dehydroprolyl-NH-CH(2)-aryl-C(=NH)NH(2) are described together with their ecarin clotting time (ECT) prolongation as measure for thrombin inhibition ex vivo. The aryl P1-moiety mimicking the arginine part of the d-Phe-Pro-Arg derived thrombin inhibitors turned out to be a key component for in vitro potency and in vivo activity. Optimization of this part led to compounds with improved antithrombin activity in rats and dogs after oral administration compared to the recently launched anticoagulant melagatran.


Assuntos
Antitrombinas/farmacologia , Administração Oral , Animais , Antitrombinas/administração & dosagem , Antitrombinas/química , Cães , Modelos Moleculares , Ratos , Relação Estrutura-Atividade , Difração de Raios X
7.
Bioorg Med Chem Lett ; 16(10): 2648-53, 2006 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-16460939

RESUMO

Synthesis and SAR of orally active thrombin inhibitors of the d-Phe-Pro-Arg type with focus on the P2-moiety are described. The unexpected increase in in vitro potency, oral bioavailability, and in vivo activity of inhibitors with dehydroproline as P2-isostere is discussed. Over a period of 24h the antithrombin activity of the most active inhibitors with IC(50)s in the nanomolar range was determined in dogs demonstrating high thrombin inhibitory activity in plasma and an appropriate duration of action after oral administration.


Assuntos
Antitrombinas/farmacologia , Administração Oral , Animais , Antitrombinas/administração & dosagem , Antitrombinas/síntese química , Antitrombinas/farmacocinética , Disponibilidade Biológica , Cães , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 15(24): 5567-73, 2005 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-16219465

RESUMO

Novel 5-HT(1) autoreceptor ligands based on the N-4-aryl-piperazinyl-N'-ethyl-5,6,7,8-tetrahydropyrido[4', 3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT(1A) and 5-HT(1B) receptors. Strategies for the development of dual 5-HT(1A) and 5-HT(1B) antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT(1A) and the 5-HT(1B) receptors and was characterized further with respect to selectivity, electrically stimulated [(3)H]5-HT release and in vivo efficacy.


Assuntos
Antidepressivos/síntese química , Antagonistas do Receptor 5-HT1 de Serotonina , Antidepressivos/química , Antidepressivos/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Cinética , Modelos Moleculares , Piperazinas/química , Piperazinas/farmacologia , Relação Estrutura-Atividade
9.
Bioorg Med Chem Lett ; 13(12): 2029-33, 2003 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-12781189

RESUMO

Synthesis of thrombin inhibitors and their binding mode to thrombin is described. Modification of the P1 moiety leads to an increased selectivity versus trypsin. The observed selectivity is discussed in view of their thrombin-inhibitor complex X-ray structures.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Trombina/antagonistas & inibidores , Cristalografia por Raios X , Desenho de Fármacos , Modelos Moleculares , Relação Estrutura-Atividade , Especificidade por Substrato , Trombina/metabolismo , Inibidores da Tripsina/química , Inibidores da Tripsina/farmacologia
10.
Bioorg Med Chem Lett ; 13(10): 1721-4, 2003 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-12729650

RESUMO

A new solid-phase synthesis for ET receptor antagonists suitable for automation is presented. A support bound 2-hydroxybutyric acid derivative was converted to the corresponding ether derivatives using 4-halo-2-methylsulfonylpyrimidines. Subsequent Suzuki coupling with various aryl boronic acids gave the desired antagonists in good yields and purities. Highly potent antagonists with excellent selectivity for ET(A) were obtained.


Assuntos
Butiratos/síntese química , Antagonistas dos Receptores de Endotelina , Pirimidinas/síntese química , Animais , Butiratos/farmacologia , Células CHO , Técnicas de Química Combinatória , Cricetinae , Endotelina-1/metabolismo , Humanos , Ligação Proteica , Pirimidinas/farmacologia , Radioimunoensaio , Receptores de Endotelina/genética , Receptores de Endotelina/metabolismo , Resinas Sintéticas , Relação Estrutura-Atividade , Transfecção
11.
Bioorg Med Chem ; 11(7): 1319-41, 2003 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-12628659

RESUMO

The design and synthesis of novel integrin alpha(V)beta(3) antagonists based on a 1,5- or 2,5-substituted tetrahydrobenzaezpinone core is described. In vitro activity of respective compounds was determined via alpha(V)beta(3) binding assay, and selected derivatives were submitted to further characterization in functional cellular assays. SAR was obtained by modification of the benzazepinone core, variation of the spacer linking guanidine moiety and core, and modification of the guanidine mimetic. These efforts led to the identification of novel alpha(V)beta(3) inhibitors displaying potency in the subnanomolar range, selectivity versus alpha(IIb)beta(3) and functional efficacy in relevant cellular assays. A method for the preparation of enantiomerically pure derivatives was developed, and respective enantiomers evaluated in vitro. Compounds 31 and 37 were assessed for metabolic stability, resorption in the Caco-2 assay and pharmacokinetics.


Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Integrina alfaVbeta3/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacologia , Animais , Células CACO-2 , Adesão Celular/efeitos dos fármacos , Cristalografia por Raios X , Desenho de Fármacos , Ensaio de Imunoadsorção Enzimática , Feminino , Guanidina/química , Humanos , Técnicas In Vitro , Indicadores e Reagentes , Integrina alfa4beta1/antagonistas & inibidores , Espectroscopia de Ressonância Magnética , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Conformação Molecular , Placenta/efeitos dos fármacos , Placenta/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Ratos , Estereoisomerismo , Relação Estrutura-Atividade
12.
Bioorg Med Chem Lett ; 13(2): 165-9, 2003 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-12482416

RESUMO

Solid-phase synthesis and SAR of alpha(V)beta(3)-receptor antagonists based on a N(1)-substituted 4-amino-1H-pyrimidin-2-one scaffold are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta(3) in the nano- to subnanomolar range and high selectivity versus related integrins like alpha(IIb)beta(3). For selected examples efficacy in functional cellular assays was demonstrated.


Assuntos
Integrina alfaVbeta3/antagonistas & inibidores , Pirimidinonas/síntese química , Pirimidinonas/farmacologia , Técnicas de Química Combinatória , Ensaio de Imunoadsorção Enzimática , Guanidinas/farmacologia , Indicadores e Reagentes , Ligantes , Mimetismo Molecular , Relação Estrutura-Atividade
13.
Bioorg Med Chem Lett ; 12(12): 1571-3, 2002 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-12039564

RESUMO

A newly developed convergent solid-phase synthesis provides efficient access to thrombin inhibitors of the D-Phe-Pro-Arg type. Members of the synthesized libraries inhibited thrombin with IC(50)s in the nanomolar range.


Assuntos
Antitrombinas/síntese química , Antitrombinas/metabolismo , Sítios de Ligação , Cromatografia Líquida de Alta Pressão , Espectrofotometria Ultravioleta , Trombina/metabolismo
14.
Bioorg Med Chem Lett ; 12(10): 1379-82, 2002 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-11992781

RESUMO

Solid-phase synthesis and SAR of integrin alpha(V)beta3-receptor antagonists containing a urea moiety as non-basic guanidine mimetic are described. The most potent compounds exhibited IC(50) values towards alpha(V)beta3 in the nanomolar range and high selectivity versus related integrins like alpha(IIb)beta3. For selected examples efficacy in functional cellular assays is demonstrated.


Assuntos
Adesão Celular/efeitos dos fármacos , Receptores de Vitronectina/antagonistas & inibidores , Ureia/análogos & derivados , Ureia/síntese química , Animais , Células CHO , Cricetinae , Desenho de Fármacos , Humanos , Modelos Moleculares , Conformação Molecular , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Relação Estrutura-Atividade , Ureia/farmacologia
15.
Bioorg Med Chem Lett ; 12(3): 441-6, 2002 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-11814816

RESUMO

Synthesis and SARs of new integrin alpha(V)beta(3) antagonists based on an N-substituted dibenzazepinone scaffold are described. Variation of spacer and guanidine mimetic led to potent compounds exhibiting an IC(50) towards alpha(V)beta(3) in the nanomolar range, high selectivity versus integrin alpha(IIb)beta(3) and efficacy in functional cellular assays.


Assuntos
Dibenzazepinas/síntese química , Dibenzazepinas/farmacologia , Fibrinolíticos/síntese química , Receptores de Vitronectina/antagonistas & inibidores , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Fibrinolíticos/farmacologia , Guanidina/química , Indicadores e Reagentes , Espectrometria de Massas , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Relação Estrutura-Atividade
16.
Angew Chem Int Ed Engl ; 37(8): 1103-1107, 1998 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29711023

RESUMO

Slow addition of a primary amine to the reaction mixture greatly increases the scope of the titanium-catalyzed asymmetric reduction of imines 1. An important added feature of this method is that chiral secondary amines 2 can be obtained in much higher optical purity (up to 99 % ee) than would be predicted from the E:Z ratios of the starting imines 1.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...