3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 3: Synthesis, metabolic stability, and biological evaluation of optically active analogs

被引：6

作者：

Asada, Masaki ^{[1
]}

Obitsu, Tetsuo ^{[1
]}

Kinoshita, Atsushi ^{[1
]}

Nagase, Toshihiko ^{[1
]}

Yoshida, Tadahiro ^{[1
]}

Yamaura, Yoshiyuki ^{[1
]}

Takizawa, Hiroya ^{[1
]}

Yoshikawa, Ken ^{[1
]}

Sato, Kazutoyo ^{[1
]}

Narita, Masami ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

Tobe, Yoshito ^{[2
]}

机构：

[1] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka 6188585, Japan

[2] Osaka Univ, Grad Sch Engn, Div Frontier Mat Sci, Osaka 5608531, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 09期

关键词：

Prostaglandin; EP3; receptor; Antagonist; Uterine contraction; MICE LACKING;

D O I：

10.1016/j.bmc.2010.03.028

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

A series of 3-(2-aminocarbonylphenyl)propanoic acid analogs possessing the (1R)-1-(3,5-dimethylphenyl)-3-methylbutylamine moiety on the carboxyamide side chain were synthesized and evaluated for their binding affinity for the EP1-4 receptors and their antagonist activity for the EP3 receptor. Rational drug design based on the structure of the metabolites in human liver microsomes led us to the discovery of another series of analogs. Several compounds were further evaluated for their in vivo efficacy in rats after oral administration and also for their pharmacokinetic profiles including in vitro stability in the liver microsomes. (c) 2010 Published by Elsevier Ltd.

引用

页码：3212 / 3223

页数：12

共 15 条

[1] 3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 2: Optimization of the side chains to improve in vitro and in vivo potencies
Asada, Masaki
Iwahashi, Maki
Obitsu, Tetsuo
Kinoshita, Atsushi
Nakai, Yoshihiko
Onoda, Takahiro
Nagase, Toshihiko
Tanaka, Motoyuki
Yamaura, Yoshiyuki
Takizawa, Hiroya
Yoshikawa, Ken
Sato, Kazutoyo
Narita, Masami
Ohuchida, Shuichi
Nakai, Hisao
Toda, Masaaki
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (04) : 1641 - 1658
[2] 3-(2-Aminocarbonylphenyl)propanoic acid analogs as potent and selective EP3 receptor antagonists. Part 1: Discovery and exploration of the carboxyamide side chain
Asada, Masaki
Obitsu, Tetsuo
Nagase, Toshihiko
Tanaka, Motoyuki
Yamaura, Yoshiyuki
Takizawa, Hiroya
Yoshikawa, Ken
Sato, Kazutoyo
Narita, Masami
Ohuchida, Shuichi
Nakai, Hisao
Toda, Masaaki
[J]. BIOORGANIC & MEDICINAL CHEMISTRY, 2010, 18 (01) : 80 - 90
[3] *CCDC, 768381 CCDC
[4] PROSTANOID INHIBITION OF CANINE PARIETAL-CELLS - MEDIATION BY THE INHIBITORY GUANOSINE TRIPHOSPHATE-BINDING PROTEIN OF ADENYLATE-CYCLASE
CHEN, MCY
AMIRIAN, DA
TOOMEY, M
SANDERS, MJ
SOLL, AH
[J]. GASTROENTEROLOGY, 1988, 94 (05) : 1121 - 1129
[5] CORGAN DE, 1999, TETRAHEDRON, V55, P8883
[6] Synthesis of diaryl ethers through the copper-promoted arylation of phenols with arylboronic acids. An expedient synthesis of thyroxine
Evans, DA
Katz, JL
West, TR
[J]. TETRAHEDRON LETTERS, 1998, 39 (19) : 2937 - 2940
[7] Cerium(IV) ammonium nitrate mediated nitration of coumarins
Ganguly, N
Sukai, AK
De, S
[J]. SYNTHETIC COMMUNICATIONS, 2001, 31 (02) : 301 - 309
[8] Vascular wall-produced prostaglandin E2 exacerbates arterial thrombosis and atherothrombosis through platelet EP3 receptors
Gross, Sabrina
Tilly, Peggy
Hentsch, Didier
Vonesch, Jean-Luc
Fabre, Jean-Etienne
[J]. JOURNAL OF EXPERIMENTAL MEDICINE, 2007, 204 (02) : 311 - 320
[9] Copper-catalyzed general C-N and C-O bond cross-coupling with arylboronic acid
Lam, PYS
Vincent, G
Clark, CG
Deudon, S
Jadhav, PK
[J]. TETRAHEDRON LETTERS, 2001, 42 (20) : 3415 - 3418
[10] Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E receptor subtype EP3
Ma, H
Hara, A
Xiao, CY
Okada, Y
Takahata, O
Nakaya, K
Sugimoto, Y
Ichikawa, A
Narumiya, S
Ushikubi, F
[J]. CIRCULATION, 2001, 104 (10) : 1176 - 1180

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