Design and synthesis of indomethacin analogues that inhibit P-glycoprotein and/or multidrug resistant protein without COX inhibitory activity.
We designed and synthesized conformationally restricted analogues and regioisomers of the nonsteroidal anti-inflammatory drug indomethacin. Evaluation of the inhibitory effects of these compounds on COX, P-glycoprotein, and multidrug resistance indicated that NSAIDS modulation of multidrug-resistant P-glycoprotein and multidrug-resistant protein-1 is not associated with COX-1 and COX-2 inhibitory activities.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Sapporo 060-0812, Japan. arisawa@pharm.hokudai.ac.jp
Mitsuhiro
M
Arisawa
Yayoi
Y
Kasaya
Tohru
T
Obata
Takuma
T
Sasaki
Tomonori
T
Nakamura
Takuya
T
Araki
Koujirou
K
Yamamoto
Akito
A
Sasaki
Akihito
A
Yamano
Mika
M
Ito
Hiroshi
H
Abe
Yoshihiro
Y
Ito
Satoshi
S
Shuto
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D060326:Chemistry Techniques, Synthetic; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D018432:Drug Resistance, Multiple / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D007213:Indomethacin