Synthesis and structure-activity relationship of tetrahydropyrazolopyrimidine derivatives--a novel structural class of potent calcium-sensing receptor antagonists.
A series of novel tetrahydropyrazolopyrimidine derivatives containing an adamantyl group were synthesized and evaluated as potential calcium-sensing receptor (CaSR) antagonists. After chemical modification of 9a, which was identified as a hit compound in a random screening of CaSR antagonist assay, 7,7-dimethyl derivative 16c was found to be the most active compound of this new series (IC(50)=10nM). We report the synthesis of this series and their biological activities and structure-activity relationship.
Pharmacutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi-2-chome, Yodogawa-ku, Osaka 532-8686, Japan. Yoshida_Masato@takeda.co.jp
Masato
M
Yoshida
Akira
A
Mori
Atsuhiro
A
Inaba
Masahiro
M
Oka
Haruhiko
H
Makino
Masashi
M
Yamaguchi
Hisashi
H
Fujita
Tomohiro
T
Kawamoto
Mika
M
Goto
Hiroyuki
H
Kimura
Atsuo
A
Baba
Tsuneo
T
Yasuma
D000218:Adamantane / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D020128:Inhibitory Concentration 50; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D044169:Receptors, Calcium-Sensing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011743:Pyrimidines; D044169:Receptors, Calcium-Sensing; D000218:Adamantane