Synthesis, biological activity and molecular modeling studies of novel COX-1 inhibitors.
Synthesis of new potential COX-1 and/or COX-2 inhibitors, derivatives of 1,1-di-(3-carboxyphenyl)ethane, their biological activity, docking results on COX-1 enzyme and absorption, distribution, metabolism, excretion (ADME) properties are presented. In addition to known interactions between ketoprofen and ibuprofen, leading NSAID agents and COX-1 active site, the possibility of formation of additional interactions is explored. Interactions with Ala527, and with one of the water molecules situated within the active site are identified. Molecular mechanics and DFT calculations for studied compounds have revealed free rotation around two central bonds (C1-C3' and C1-C3"), making them flexible, thus easier to enter and adjust to the active site. Further modifications of core structure have been undertaken to optimize biological activity and ADME properties. As a result, two of the compounds are indicated as novel COX-1 inhibitors.
Martić
Miljen
M
PLIVA Pharmaceutical Industry, Incorporated, Prilaz Baruna Filipovića 25, 10000 Zagreb, Croatia.
Tatić
Iva
I
Marković
Stribor
S
Kujundzić
Nedjeljko
N
Kostrun
Sanja
S
D000327:Adsorption; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D001682:Biological Availability; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D004980:Ethane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007052:Ibuprofen / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007660:Ketoprofen / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D011451:Prostaglandin-Endoperoxide Synthases; D013329:Structure-Activity Relationship
C492565:1,1-di-(3-carboxyphenyl)ethane; D001565:Benzoates; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D008024:Ligands; D007660:Ketoprofen; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D004980:Ethane; D007052:Ibuprofen