Discovery of Orally Available 8-Aza-5-thiaProstaglandin E1 Analogs as Highly Selective EP4 Agonists

被引：9

作者：

Kambe, Tohru ^{[1
]}

Maruyama, Toru ^{[1
]}

Nakano, Masayuki ^{[1
]}

Yamaura, Yoshiyuki ^{[1
]}

Shono, Tomoyuki ^{[1
]}

Seki, Akiteru ^{[1
]}

Sakata, Kiyoto ^{[1
]}

Maruyama, Takayuki ^{[1
]}

Nakai, Hisao ^{[1
]}

Toda, Masaaki ^{[1
]}

机构：

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

来源：

CHEMICAL & PHARMACEUTICAL BULLETIN | 2011年 / 59卷 / 12期

关键词：

prostaglandin; agonist; EP4-receptor; tumor necrosis factor-alpha; RECEPTOR AGONISTS; LACTAMS;

D O I：

10.1248/cpb.59.1523

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Analogs 8-aza-16-aryl prostaglandin E-1 (PGE(1)) and 8-aza-5-thia-16-arylPGE(1) were synthesized and evaluated with respect to their subtype receptor affinity and EP4 agonist activity for the purposes of identifying subtype-selective EP4 agonists that demonstrate oral efficacy. Using an inhibition assay of lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-alpha production in rats, representative compounds were evaluated for their pharmacokinetic profiles and in vivo efficacy. Structure-activity relationships (SARs) were characterized and presented. Of the compounds tested, several demonstrated better oral exposure and/or in vivo efficacy compared with the previously reported analog 2a.

引用

页码：1523 / 1534

页数：12

共 9 条

[1] Discovery of a potent and selective agonist of the prostaglandin EP4 receptor [J].

Billot, X ;

Chateauneuf, A ;

Chauret, N ;

Denis, D ;

Greig, G ;

Mathieu, MC ;

Metters, KM ;

Slipetz, DM ;

Young, RN .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2003, 13 (06) :1129-1132

[2] Discovery of highly selective EP4 receptor agonists that stimulate new bone formation and restore bone mass in ovariectomized rats [J].

Cameron, KO ;

Lefker, BA ;

Chu-Moyer, MY ;

Crawford, DT ;

Jardine, PD ;

DeNinno, SL ;

Gilbert, S ;

Grasser, WA ;

Ke, HZ ;

Lu, BH ;

Owen, TA ;

Paralkar, VM ;

Qi, H ;

Scott, DO ;

Thompson, DD ;

Tjoa, CM ;

Zawistoski, MP .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (07) :1799-1802

[3]

COLEMAN RA, 1994, PHARMACOL REV, V46, P205

[4] Lactams as EP4 prostanoid receptor agonists.: 3.: Discovery of N-ethylbenzoic acid 2-pyrrolidinones as subtype selective agents [J].

Elworthy, TR ;

Brill, ER ;

Chiou, SS ;

Chu, F ;

Harris, JR ;

Hendricks, RT ;

Huang, J ;

Kim, W ;

Lach, LK ;

Mirzadegan, T ;

Yee, C ;

Walker, KAM .

JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (25) :6124-6127

[5] Lactams as EP4 prostanoid receptor subtype selective agonists.: Part 1:2-pyrrolidinones-stereochemical and lower side-chain optimization [J].

Elworthy, TR ;

Kertesz, DJ ;

Kim, WK ;

Roepel, MG ;

Quattrocchio-Setti, L ;

Smith, DB ;

Tracy, JL ;

Chow, A ;

Li, FJ ;

Brill, ER ;

Lach, LK ;

McGee, D ;

Yang, DS ;

Chiou, SS .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2004, 14 (07) :1655-1659

[6] Discovery of an 8-Aza-5-thiaProstaglandin E1 Analog as a Highly Selective EP4 Receptor Agonist [J].

Kambe, Tohru ;

Maruyama, Toru ;

Naganawa, Atsushi ;

Asada, Masaki ;

Seki, Akiteru ;

Maruyama, Takayuki ;

Nakai, Hisao ;

Toda, Masaaki .

CHEMICAL & PHARMACEUTICAL BULLETIN, 2011, 59 (12) :1494-1508

[7] Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist [J].

Maruyama, T ;

Kuwabe, SI ;

Kawanaka, Y ;

Shiraishi, T ;

Shinagawa, Y ;

Sakata, K ;

Seki, A ;

Kishida, Y ;

Yoshida, H ;

Maruyama, T ;

Ohuchida, S ;

Nakai, H ;

Hashimoto, S ;

Kawamura, M ;

Kondo, K ;

Toda, M .

BIOORGANIC & MEDICINAL CHEMISTRY, 2002, 10 (07) :2103-2110

[8] STUDIES ON THE SYNTHESIS OF FURANS BY ANIONIC CYCLIZATION OF 4-PENTYNONES [J].

VIESER, R ;

EBERBACH, W .

TETRAHEDRON LETTERS, 1995, 36 (25) :4405-4408

[9] Syntheses of steroidal vinyl ethers using palladium acetate-phenanthroline as catalyst [J].

Weintraub, PM ;

King, CHR .

JOURNAL OF ORGANIC CHEMISTRY, 1997, 62 (05) :1560-1562

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