RESUMO
With the aim to discover a novel potent potassium-competitive acid blocker (P-CAB) agent, a series of 5-methyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole derivatives were synthesized, and their H+/K+-ATPase inhibitory activities and inhibitory action on histamine-stimulated gastric acid secretion in rats were evaluated. Among the compounds synthesized, compound 3'-((3-(2-fluorophenyl)-5-methyl-5,6-dihydropyrrolo[3,4-c]pyrazol-2(4H)-yl)methyl)-[1,1'-biphenyl]-3-carboxamide not only exhibited potent H+/K+-ATPase inhibitory activity but olso showed potent inhibitory action in vivo on histamine-stimulated gastric acid secretion. In addition, the lead compound displayed favourable oral pharmacokinetic properties in rats, which was worthy of further study as a novel P-CAB agent.
Assuntos
Ácido Gástrico , ATPase Trocadora de Hidrogênio-Potássio , Animais , Ácido Gástrico/metabolismo , ATPase Trocadora de Hidrogênio-Potássio/metabolismo , Histamina , Potássio/metabolismo , Inibidores da Bomba de Prótons/farmacologia , Pirazóis/farmacologia , Pirróis/farmacologia , RatosRESUMO
Two series of novel tricyclic oxazine and oxazepine fused quinazolines have been designed and synthesized. The in vitro antitumor effect of the title compounds was screened on N87, A431, H1975, BT474 and Calu-3 cell lines. Compared to gefitinib and erlotinib, compounds 1a-1h were found to demonstrate more potent antitumor activities. Several derivatives could counteract EGF-induced phosphorylation of EGFR in cells, and their potency was comparable to the reference compounds. Compounds 1a-1f, 1h were chosen for further evaluation of EGFR and HER2 in vitro kinase inhibitory activity. Compounds 1c-1f, 1h effectively inhibited the in vitro kinase activity of EGFR and HER2 with similar efficacy as gefitinib and erlotinib.
Assuntos
Quinazolinas/química , Quinazolinas/farmacologia , Linhagem Celular , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Gefitinibe , Humanos , FosforilaçãoRESUMO
The title compound, C(21)H(26)NO(4) (+)·Br(-), also known as R-methyl-naltrexone (MNTX) bromide, is a selective peripher-ally acting µ-opioid receptor antagonist with a oroxymorphone skeleton, synthesized by hydroxyl protection, N-methyl-ation, deprotection and anion exchange of naltrexone. It comprises a five-ring system A/B/C/D/E. Rings C and E adopt distorted chair conformations, whereas ring D is in half-chair conformation. The C/E ring junctions are trans fused. The dihedral angle between rings D and E is 82.3â (1)°, while the dihedral angles between the planes of rings C and A, and rings D and E are respectively 81.7â (1), 75.9â (1) and 12.2â (1)°. In the crystal, mol-ecules are linked by O-Hâ¯Br hydrogen bonds.