Novel pyrazolo[1,5-a]pyridines as orally active EP1receptor antagonists: Synthesis, structure-activity relationship studies, and biological evaluation.
Novel pyrazolo[1,5-a]pyridine derivatives were designed, synthesized and evaluated as orally active EP1antagonists for the treatment of overactive bladder. Matched molecular pair analysis (MMPA) allowed the design of a new series of pyrazolo[1,5-a]pyridine derivatives 4-6. Structure-activity relationships (SAR) studies of 4-6 were performed, leading to identification of the nanomolar-level EP1antagonist 4c, which exhibited good pharmacological effect through intraduodenal (id) administration in a 17-phenyltrinor prostaglandin E2-induced bladder contraction model in rats.
Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Kentaro
K
Umei
Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Yosuke
Y
Nishigaya
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan.
Atsushi
A
Kondo
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan.
Kazuya
K
Tatani
Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino, Nagano 399-8304, Japan.
Nobuyuki
N
Tanaka
Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan.
Yasushi
Y
Kohno
Watarase Research Center, Discovery Research Headquarters, Kyorin Pharmaceutical Co., Ltd., 1848, Nogi, Nogi-machi, Shimotsuga-gun, Tochigi 329-0114, Japan. Electronic address: shigeki.seto@mb.kyorin-pharm.co.jp.
Shigeki
S
Seto
D000818:Animals; D002460:Cell Line; D008297:Male; D011720:Pyrazoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017208:Rats, Wistar; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D053201:Urinary Bladder, Overactive / Q000188:drug therapy
C000625357:1-((5-chloro-2-phenylpyrazolo(1,5-a)pyridin-7-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylic acid; D011720:Pyrazoles; D011725:Pyridines; D058306:Receptors, Prostaglandin E, EP1 Subtype
EP(1) antagonist; Matched molecular pair; Pyrazolo[1,5-a]pyridine; Structure-activity relationships