RESUMO
Novel indole-3-thio-, 3-sulfonyl- and 3-oxy-aryl-1-acetic acids are reported which are potent, selective antagonists of the chemoattractant receptor-homologous expressed on Th2 lymphocytes receptor (CRTh2 or DP2). Optimization required maintenance of high CRTh2 potency whilst achieving a concomitant reduction in rates of metabolism, removal of cyp p450 inhibition and minimization of aldose reductase and aldehyde reductase activity. High quality compounds suitable for in vivo studies are highlighted, culminating in the discovery of AZD1981 (22).
Assuntos
Acetatos/farmacologia , Descoberta de Drogas , Ácidos Indolacéticos/farmacologia , Indóis/farmacologia , Receptores Imunológicos/antagonistas & inibidores , Receptores de Prostaglandina/antagonistas & inibidores , Acetatos/química , Humanos , Ácidos Indolacéticos/química , Indóis/química , Neutrófilos/efeitos dos fármacosRESUMO
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
Assuntos
Isoxazóis/síntese química , Transportadores de Ácidos Monocarboxílicos/antagonistas & inibidores , Transportadores de Ácidos Monocarboxílicos/química , Naftalenos/síntese química , Pirrolidinas/síntese química , Quinolinas/síntese química , Simportadores/antagonistas & inibidores , Simportadores/química , Tiazolidinas/síntese química , Isomerismo , Isoxazóis/química , Cinética , Espectroscopia de Ressonância Magnética , Conformação Molecular , Naftalenos/química , Pirrolidinas/química , Quinolinas/química , Tiazolidinas/químicaRESUMO
Lithiation of N-benzyl pyridine and quinoline carboxamides alpha to nitrogen gives anions that undergo intramolecular attack on the pyridine or quinoline ring, either directly or on activation of the ring by N-acylation. The resulting four-, five-, or six-membered-ring-containing compound may be oxidized, protonated, alkylated, or acylated to give a range of polycyclic heterocycles, including pyrrolopyridines, pyrroloquinolines, benzonaphthyridines, and azaspirocyclic beta-lactams. [reaction: see text]
