RESUMO
An X-ray crystal structure of Kelch-like ECH-associated protein (Keap1) co-crystallised with (1S,2R)-2-[(1S)-1-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]-1,2,3,4-tetrahydroisoquinolin-2-carbonyl]cyclohexane-1-carboxylic acid (compound (S,R,S)-1 a) was obtained. This X-ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)-1 a, as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas do Citoesqueleto/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Isoquinolinas/farmacologia , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Ftalimidas/farmacologia , Animais , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Humanos , Isoquinolinas/síntese química , Isoquinolinas/química , Proteína 1 Associada a ECH Semelhante a Kelch , Camundongos , Modelos Moleculares , Estrutura Molecular , Ftalimidas/síntese química , Ftalimidas/química , Relação Estrutura-AtividadeRESUMO
A series of potent and subtype selective H3 receptor antagonists containing a novel tetrazole core and diamine motif is reported. A one-pot multi-component Ugi reaction was utilised to rapidly develop the structure-activity relationships (SAR) of these compounds. Optimisation for liver microsome stability (t(1/2)>60 min), minimal CYP inhibition (IC(50)>50 microM) and high cell permeability (Caco-2 P(app) >20x10(-6) cm/s) identified several compounds with drug-like properties.
Assuntos
Antagonistas dos Receptores Histamínicos H3/farmacologia , Tetrazóis/farmacologia , Células CACO-2 , Permeabilidade da Membrana Celular , Descoberta de Drogas , Meia-Vida , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Humanos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/metabolismo , Relação Estrutura-Atividade , Tetrazóis/química , Tetrazóis/farmacocinéticaRESUMO
The combination of catalytic amounts of [Pd(PPh3)4], copper thiophene-2-carboxylate (CuTC) and [Ph2PO2][NBu4] allowed a series of exigent Stille-Migita reactions to be performed with high yields; as the protocol is fluoride free, a variety of O-silyl and C-silyl groups remained intact.
Assuntos
Reagentes de Ligações Cruzadas/química , Catálise , Cobre/química , Estrutura Molecular , Paládio/químicaRESUMO
Directed metallation and sulfinylation yields sulfoxides which undergo ipso nucleophilic aromatic substitution with tertiary and secondary alkyllithiums, giving aromatic rings bearing alkyl groups generally incompatible with directed metallation methods and with regioselectivity complementary with classical Friedel-Crafts substitution.
Assuntos
Enxofre/química , Tiocarbamatos/química , Benzamidas/química , Estrutura MolecularRESUMO
Tertiary aromatic amides bearing stereogenic centres ortho to the amide group may adopt two diastereoisomeric conformations which interconvert slowly on the NMR timescale at ambient temperature, and are therefore detectable by NMR. Certain classes of stereogenic centre--particularly sulfoxides, ephedrine-derived oxazolidines, and proline-derived imidazolidines--strongly bias the population of the two conformers. We propose a model, supported by molecular mechanics calculations, which rationalises the sense and magnitude of the conformational selectivity attained in terms of the steric and electronic properties of the controlling centre. The control over conformation may be exploited either by trapping the favoured conformer as an atropisomer, or by using it to relay information about the stereochemistry of the controlling centre.
Assuntos
Amidas/química , Modelos Químicos , Alquilação , Cristalografia por Raios X , Efedrina/química , Hidroxilação , Cinética , Espectroscopia de Ressonância Magnética , Conformação Molecular , Oxazóis/química , Prolina/química , Estereoisomerismo , Enxofre/química , TermodinâmicaRESUMO
Tertiary 1-naphthamides racemise much more slowly than their laterally lithiated derivatives, and the relative rates of racemisation and epimerisation of these derivatives indicate that the lithium-bearing stereogenic centre inverts via a "conducted tour" mechanism, in which the lithium cation is delivered from one face to the other by coordination to the rotating amide group.