Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 32
Filtrar
1.
J Chem Inf Model ; 57(2): 159-169, 2017 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-28080056

RESUMO

The duration of drug efficacy in vivo is a key aspect primarily addressed during the lead optimization phase of drug discovery. Hence, the availability of robust computational approaches that can predict the residence time of a compound at its target would accelerate candidate selection. Nowadays the theoretical prediction of this parameter is still very challenging. Starting from methods reported in the literature, we set up and validated a new metadynamics (META-D)-based protocol that was used to rank the experimental residence times of 10 arylpyrazole cyclin-dependent kinase 8 (CDK8) inhibitors for which target-bound X-ray structures are available. The application of reported methods based on the detection of the escape from the first free energy well gave a poor correlation with the experimental values. Our protocol evaluates the energetics of the whole unbinding process, accounting for multiple intermediates and transition states. Using seven collective variables (CVs) encoding both roto-translational and conformational motions of the ligand, a history-dependent biasing potential is deposited as a sum of constant-height Gaussian functions until the ligand reaches an unbound state. The time required to achieve this state is proportional to the integral of the deposited potential over the CV hyperspace. Average values of this time, for replicated META-D simulations, provided an accurate classification of CDK8 inhibitors spanning short, medium, and long residence times.


Assuntos
Quinase 8 Dependente de Ciclina/antagonistas & inibidores , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/farmacologia , Quinase 8 Dependente de Ciclina/química , Conformação Proteica , Inibidores de Proteínas Quinases/farmacocinética , Termodinâmica , Fatores de Tempo
2.
J Chem Inf Model ; 54(11): 3124-36, 2014 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-25299731

RESUMO

A detailed atomistic description of the unbinding process of sorafenib and sunitinib, two known VEGFR2 inhibitors clinically used to treat renal cell carcinoma, was unraveled by using steered molecular dynamics (SMD) simulations. While sunitinib is a fast-dissociating binder, sorafenib exhibits quite a long residence time at this enzyme, which might impact its duration of action in vivo. In order to gain insights into the kinetically different behaviors of the two inhibitors, an SMD study was carried out, which involved a careful optimization of the force and velocity parameters. We were able to identify two different binding pathways for the two inhibitors, as sunitinib exited the ATP binding site from the cavity entrance without a rupture point while sorafenib moved opposite to the ATP binding site entrance. Furthermore, the calculated ΔGoff values clearly reflect on a qualitative level the distinct off-rates of the two inhibitors, thus suggesting that this protocol could be tried on other VEGFR2 ligands to assess its robustness and then used to rank structural analogues of these derivatives.


Assuntos
Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Domínio Catalítico , Humanos , Indóis/metabolismo , Indóis/farmacologia , Pirróis/metabolismo , Pirróis/farmacologia , Sunitinibe , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/química
3.
J Med Chem ; 67(13): 11103-11124, 2024 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-38907711

RESUMO

A hit-to-lead campaign pursuing the identification of novel inhalant small-molecule phosphatidylinositol 3-kinase (PI3K) inhibitors for the treatment of inflammatory respiratory diseases is disclosed. A synthetically versatile pyridazin-3(2H)-one scaffold was designed, and three exit vectors on the core moiety were used to explore chemical diversity and optimize pharmacological and absorption, distribution, metabolism, and excretion (ADME) properties. Desired modulation of PI3Kδ selectivity and cellular potency as well as ADME properties in view of administration by inhalation was achieved. Intratracheal administration of lead compound 26 resulted in a promising pharmacokinetic profile, thus demonstrating that the optimization strategy of in vitro profiles successfully translated to an in vivo setting.


Assuntos
Classe I de Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Piridazinas , Animais , Humanos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/síntese química , Administração por Inalação , Piridazinas/química , Piridazinas/farmacologia , Piridazinas/farmacocinética , Piridazinas/síntese química , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Relação Estrutura-Atividade , Descoberta de Drogas , Ratos , Camundongos , Masculino , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/farmacocinética , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/administração & dosagem
4.
Eur J Med Chem ; 254: 115331, 2023 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-37094451

RESUMO

PI3Kδ is a lipid kinase which plays a key role in airway inflammatory conditions. Accordingly, the inhibition of PI3Kδ can be considered a valuable strategy for the treatment of chronic respiratory diseases such as Asthma and Chronic obstructive pulmonary disease (COPD). In this work, we describe our efforts to identify new PI3Kδ inhibitors following an "inhalation by design" strategy. Starting from the identification of a purine scaffold, we carried out a preliminary SAR expansion which led to the identification of a new hit characterized by a high enzymatic potency and moderate PI3Kδ selectivity. A subsequent optimization led to novel purine based derivatives with favorable in vitro ADME profiles, which might represent promising starting points for future development of new inhaled drug candidates.


Assuntos
Asma , Doença Pulmonar Obstrutiva Crônica , Humanos , Asma/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Administração por Inalação , Purinas/farmacologia , Purinas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases
5.
J Med Chem ; 66(8): 5622-5656, 2023 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-37017110

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.


Assuntos
Fibrose Pulmonar Idiopática , Receptores de Ácidos Lisofosfatídicos , Humanos , Lisofosfolipídeos
7.
Bioorg Med Chem Lett ; 21(18): 5423-7, 2011 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-21824774

RESUMO

The introduction of the isoxazole ring as bioisosteric replacement of the acetyl group of anatoxin-a led to a new series of derivatives binding to nicotinic acetylcholine receptors. Bulkier substitutions than methyl at the 3 position of isoxazole were shown to be detrimental for the activity. The binding potency of the most interesting compounds with α1, α7 and α3ß4 receptor subtypes, was, anyway, only at micromolar level. Moreover, differently from known derivatives with pyridine, isoxazole condensed to azabicyclo ring led to no activity.


Assuntos
Receptores Nicotínicos/metabolismo , Tropanos/química , Técnicas de Química Sintética , Toxinas de Cianobactérias , Relação Dose-Resposta a Droga , Ligantes , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade
8.
J Pharmacol Exp Ther ; 335(3): 636-44, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20810618

RESUMO

NR1/NR2A is a subtype of N-methyl-d-aspartate receptors (NMDARs), which are glutamate and glycine-gated Ca(2+)-permeable channels highly expressed in the central nervous system. A high-throughput screening (HTS) campaign using human osteosarcoma (U-2 OS) cells transiently transduced with NR1/NR2A NMDAR subunits, tested in a specifically designed fluorometric imaging plate reader (FLIPR)/Ca(2+) assay, identified sulfonamide derivative series, exemplified by 3-chloro-4-fluoro-N-[(4-{[2-(phenylcarbonyl)hydrazino]carbonyl}phenyl)methyl]benzenesulfonamide (compound 1) and thiodiazole derivative N-(cyclohexylmethyl)-2-({5-[(phenylmethyl)amino]-1,3,4-thiadiazol-2-yl}thio)acetamide (compound 13) as novel NR1/NR2A receptor antagonists. Compounds 1 and 13 displayed submicromolar and micromolar potency at NR1/NR2A receptor, respectively, although they did not show activity at NR2B-containing receptor up to 50 µM concentration. Addition of 1 mM glycine, but not 1 mM l-glutamate, was able to surmount compound 1 and 13 inhibitory effects in FLIPR NR1/NR2A assay. However, compounds 1 and 13 displaced a glutamate site antagonist [(3)H]d,l-(E)-2-amino-4-propyl-5-phosphono-3-pentenoic acid ([(3)H]CGP 39653) to a greater extent than the glycine site antagonist [(3)H]3-[(E)-2-carboxy-2-phenylethenyl]-4,6-dichloro-1H-indole-2-carboxylic acid ([(3)H]MDL 105,519), in rat brain cortex binding assay. Results of FLIPR cell-based, electrophysiological, and biochemical binding assays suggest that compounds 1 and 13 are the prototypes of novel classes of NMDAR ligands, which to the best of our knowledge are the first selective antagonists at NR1/NR2A over NR1/NR2B receptor, and might constitute useful tools able to elucidate the relative role of the NR2A subunit in physiological and pathological conditions.


Assuntos
Antagonistas de Aminoácidos Excitatórios/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Ligação Competitiva , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Córtex Cerebral/citologia , Avaliação Pré-Clínica de Medicamentos/métodos , Antagonistas de Aminoácidos Excitatórios/química , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Fluorometria/métodos , Ácido Glutâmico/farmacologia , Glicina/farmacologia , Células HEK293 , Humanos , Masculino , Estrutura Molecular , N-Metilaspartato/farmacologia , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transfecção
9.
Bioorg Med Chem Lett ; 20(24): 7308-11, 2010 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-21055936

RESUMO

A new class of selective NPS antagonist was developed starting from a commercially available product identified by screening activities. Experimental NMR observations and computational experiments allowed the discovery of a new class of derivatives. 5-Phenyl-2-[2-(1-piperidinylcarbonyl)phenyl]-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-one represents a new lead compound in the NPS antagonist field.


Assuntos
Compostos Azabicíclicos/química , Imidazóis/química , Neuropeptídeos/antagonistas & inibidores , Piperidinas/química , Animais , Simulação por Computador , Desenho de Fármacos , Humanos , Imidazóis/síntese química , Imidazóis/farmacologia , Microssomos Hepáticos/metabolismo , Neuropeptídeos/metabolismo , Ratos , Termodinâmica
10.
Bioorg Med Chem Lett ; 20(15): 4561-5, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20591663

RESUMO

The pharmacophore model of in house potent and selective alpha7 nAChR positive allosteric modulators is reported. The model was used to fish out commercially-available compounds from corporate 3D databases. As a result, novel alpha7 positive modulator chemotypes were identified. A rat full PK profile of a representative compound is also described.


Assuntos
Receptores Nicotínicos/química , Regulação Alostérica , Animais , Linhagem Celular , Bases de Dados Factuais , Humanos , Isoxazóis/química , Isoxazóis/farmacocinética , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Compostos de Fenilureia/química , Compostos de Fenilureia/farmacocinética , Ratos , Receptores Nicotínicos/metabolismo , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7
11.
Bioorg Med Chem Lett ; 20(23): 7092-6, 2010 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-20951584

RESUMO

5-{2-[4-(2-Methyl-5-quinolinyl)-1-piperazinyl]ethyl}-2(1H)-quinolinones and 3,4-dihydro-2(1H)-quinolinones have been identified with different combinations of 5-HT(1) autoreceptor antagonist and hSerT potencies and excellent rat PK profiles. The availability of tool compounds with a range of profiles at targets known to play a key role in the control of synaptic 5-HT levels will allow exploration of different pharmacological profiles in a range of animal behavioral and disease models.


Assuntos
Quinolonas/química , Receptores 5-HT1 de Serotonina/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Animais , Autorreceptores/antagonistas & inibidores , Autorreceptores/efeitos dos fármacos , Quinolonas/farmacocinética , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sinapses/química
14.
J Med Chem ; 61(11): 4757-4773, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29741897

RESUMO

Inhaled corticosteroids (ICSs) represent the first line therapy for the treatment of asthma and are also extensively utilized in chronic obstructive pulmonary disease. Our goal was to develop a new ICS with a basic group, which can allow solid state feature modulation, achieving at the same time high local anti-inflammatory effect and low systemic exposure. Through a rational drug design approach, a new series of pyrrolidine derivatives of budesonide was identified. Within the series, several compounds showed nanomolar binding affinity ( Ki) with GR that mostly correlated with the effect in inducing GR nuclear translocation in CHO cells and anti-inflammatory effects in macrophagic cell lines. Binding and functional cell-based assays allowed identifying compound 17 as a potent ICS agonist with a PK profile showing an adequate lung retention and low systemic exposure in vivo. Finally, compound 17 proved to be more potent than budesonide in a rat model of acute pulmonary inflammation.


Assuntos
Corticosteroides/química , Corticosteroides/farmacologia , Budesonida/química , Budesonida/farmacologia , Desenho de Fármacos , Pneumonia/tratamento farmacológico , Administração por Inalação , Corticosteroides/farmacocinética , Corticosteroides/uso terapêutico , Animais , Budesonida/farmacocinética , Budesonida/uso terapêutico , Células CHO , Cricetulus , Humanos , Camundongos , Simulação de Acoplamento Molecular , Conformação Proteica , Células RAW 264.7 , Receptores de Glucocorticoides/química , Receptores de Glucocorticoides/metabolismo , Distribuição Tecidual
15.
J Med Chem ; 50(21): 5076-89, 2007 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-17867665

RESUMO

The discovery of new highly potent and selective dopamine D3 receptor antagonists has recently permitted characterization of the role of the dopamine D3 receptor in a wide range of preclinical animal models. A novel series of 1,2,4-triazol-3-yl-thiopropyl-tetrahydrobenzazepines demonstrating a high level of D3 affinity and selectivity with an excellent pharmacokinetic profile is reported here. In particular, the pyrazolyl derivative 35 showed good oral bioavailability and brain penetration associated with high potency and selectivity in vitro. In vivo characterization of 35 confirmed that this compound blocks the expression of nicotine- and cocaine-conditioned place preference in the rat, prevents nicotine-triggered reinstatement of nicotine-seeking behavior in the rat, reduces oral operant alcohol self-administration in the mouse, increases extracellular levels of acetylcholine in the rat medial prefrontal cortex, and potentiates the amplitude of the relative cerebral blood volume response to d-amphetamine in a regionally specific manner in the rat brain.


Assuntos
Benzazepinas/síntese química , Receptores de Dopamina D3/antagonistas & inibidores , Triazóis/síntese química , Acetilcolina/metabolismo , Administração Oral , Consumo de Bebidas Alcoólicas/prevenção & controle , Animais , Benzazepinas/farmacocinética , Benzazepinas/farmacologia , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Cobaias , Antagonistas dos Receptores Histamínicos H1/síntese química , Antagonistas dos Receptores Histamínicos H1/farmacocinética , Antagonistas dos Receptores Histamínicos H1/farmacologia , Humanos , Técnicas In Vitro , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3/agonistas , Receptores Histamínicos H1/metabolismo , Relação Estrutura-Atividade , Tabagismo/prevenção & controle , Triazóis/farmacocinética , Triazóis/farmacologia
16.
J Med Chem ; 60(10): 4304-4315, 2017 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-28489362

RESUMO

IC87114 [compound 1, (2-((6-amino-9H-purin-9-yl)methyl)-5-methyl-3-(o-tolyl)quinazolin-4(3H)-one)] is a potent PI3K inhibitor selective for the δ isoform. As predicted by molecular modeling calculations, rotation around the bond connecting the quinazolin-4(3H)-one nucleus to the o-tolyl is sterically hampered, which leads to separable conformers with axial chirality (i.e., atropisomers). After verifying that the aS and aR isomers of compound 1 do not interconvert in solution, we investigated how biological activity is influenced by axial chirality and conformational equilibrium. The aS and aR atropisomers of 1 were equally active in the PI3Kδ assay. Conversely, the introduction of a methyl group at the methylene hinge connecting the 6-amino-9H-purin-9-yl pendant to the quinazolin-4(3H)-one nucleus of both aS and aR isomers of 1 had a critical effect on the inhibitory activity, indicating that modulation of the conformational space accessible for the two bonds departing from the central methylene considerably affects the binding of compound 1 analogues to PI3Kδ enzyme.


Assuntos
Adenina/análogos & derivados , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/química , Quinazolinas/farmacologia , Adenina/química , Adenina/farmacologia , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/química , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Humanos , Isomerismo , Camundongos , Modelos Moleculares
17.
J Med Chem ; 49(20): 5912-31, 2006 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-17004707

RESUMO

Docking is a computational technique that samples conformations of small molecules in protein binding sites; scoring functions are used to assess which of these conformations best complements the protein binding site. An evaluation of 10 docking programs and 37 scoring functions was conducted against eight proteins of seven protein types for three tasks: binding mode prediction, virtual screening for lead identification, and rank-ordering by affinity for lead optimization. All of the docking programs were able to generate ligand conformations similar to crystallographically determined protein/ligand complex structures for at least one of the targets. However, scoring functions were less successful at distinguishing the crystallographic conformation from the set of docked poses. Docking programs identified active compounds from a pharmaceutically relevant pool of decoy compounds; however, no single program performed well for all of the targets. For prediction of compound affinity, none of the docking programs or scoring functions made a useful prediction of ligand binding affinity.


Assuntos
Ligantes , Proteínas/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Sítios de Ligação , Desenho de Fármacos , Modelos Moleculares , Conformação Molecular , Ligação Proteica , Software
18.
Mol Inform ; 35(8-9): 350-7, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27546039

RESUMO

The cognate docking performance of Glide was evaluated using the Astex diverse set. The standard Glide SP protocol obtained a 85.7 % success rate when the shape similarity cutoff was set to 0.625. The analysis of docking failures pointed out that, when the SiteMap binding site exposure is less than 0.491, 51 out of 52 ligands are correctly positioned. In light of this important finding, an improved docking protocol called GLIMPSED was set up. GLIMPSED relies on the standard Glide SP protocol for binding sites with low exposure, while a more accurate sampling of docking poses followed by a final MM-GBSA rescoring is performed for those highly exposed to the solvent. GLIMPSED and Glide SP were compared applying an accurate and rigorous metrics described in the literature by Hawkins et al. As a result, GLIMPSED was able to dock 89.3 % of the ligands in a correct way. Even though this number is not remarkably different from that obtained with the standard method, it is indeed statistically significant. Applying the Cohen's effect size test, a small, but not trivial, superiority of GLIMPSED was found with respect to standard Glide SP protocol. In our view the SiteMap binding site exposure parameter should be used as guideline to decide whether either a standard or a more extended docking protocol has to be adopted to predict good binding poses.


Assuntos
Proteínas/química , Proteínas/metabolismo , Algoritmos , Sítios de Ligação/fisiologia , Ligantes , Modelos Moleculares , Simulação de Acoplamento Molecular/métodos , Ligação Proteica/fisiologia , Software
19.
Chemistry ; 8(20): 4597-612, 2002 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-12362397

RESUMO

As a step to delineate a strategy of ligand design for cholera toxin (CT), NMR studies were performed on several mimics of the GM1 ganglioside oligosaccharide. The conformation of these analogues was investigated first in solution and then upon binding to cholera toxin by transferred nuclear Overhauser effect (TR-NOE) measurements. It was demonstrated that CT selects a conformation similar to the global minima of the free saccharides from the ensemble of presented conformations. No evidence of major conformational distortions was obtained, but one or two of the available conformers of the hydroxyacid side chain appear to be selected in the bound state. The NMR data were interpreted with the aid of computer models, generated and analyzed by using a combination of different approaches (MacroModels' MC/EM and MC/SD, Autodock, and GRID). Analysis of the NMR data supported by computational studies allowed us to interpret the experimental observations and to derive workable models of the ligand:toxin complexes. These models suggest that the higher affinity of the (R)-lactic acid derivative 3 may stem from lipophilic interactions with a hydrophobic area in the toxin binding site located in the vicinity of the sialic acid side chain binding region of the CT:GM1 complex, and formed by the side chain of Ile-58 and Lys-34. Thus, the models obtained have allowed us to make useful design suggestions for the improvement of ligand affinity.

20.
Farmaco ; 59(3): 175-83, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14987980

RESUMO

Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester, a potent and selective mGluR1 non-competitive antagonist, we report here a detailed exploration of the C-2 position of this scaffold with the preparation of differently substituted amides. Great improvement of the pharmacokinetic properties has been achieved through this exercise.


Assuntos
Ésteres/síntese química , Ésteres/farmacologia , Pirróis/síntese química , Pirróis/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Amidas/síntese química , Amidas/farmacocinética , Animais , Azidas/síntese química , Azidas/farmacocinética , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Cromatografia em Camada Fina , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacocinética , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Conformação Molecular , Ratos , Solubilidade , Espectrofotometria Infravermelho , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA