Development of a prostaglandin D2 receptor antagonist: discovery of a new chemical lead.
A series of N-(p-alkoxy)benzoyl-5-methoxy-2-methylindole-3-acetic acids and N-(p-butoxy)benzoyl-2-methylindole-4-acetic acid were discovered as new chemical leads for a prostaglandin D2 (PGD2) receptor antagonist. Most of them exhibited PGD2 receptor binding and blocked cyclic adenosine 3',5'-monophosphate (cAMP) formation in vitro. In particular, 2-methylindole-4-acetic acid analog 1 showed markedly increased receptor affinity and cAMP antagonist activity. Chemistry and structure activity relationship (SAR) data are also presented.
Torisu
Kazuhiko
K
Minase Research Institute, Ono Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka 618-8585, Japan. torisu@ono.co.jp
Kobayashi
Kaoru
K
Iwahashi
Maki
M
Egashira
Hiromu
H
Nakai
Yoshihiko
Y
Okada
Yutaka
Y
Nanbu
Fumio
F
Ohuchida
Shuichi
S
Nakai
Hisao
H
Toda
Masaaki
M
D000818:Animals; D019540:Area Under Curve; D001667:Binding, Competitive / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D006207:Half-Life; D007210:Indoleacetic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D007213:Indomethacin / Q000031:analogs & derivatives / Q000737:chemistry / Q000493:pharmacokinetics; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
D007210:Indoleacetic Acids; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D000242:Cyclic AMP; D007213:Indomethacin; C036293:prostaglandin D2 receptor