Discovery of orally available spirodiketopiperazine-based CCR5 antagonists

被引：15

作者：

Nishizawa, Rena ^{[1
]}

Nishiyama, Toshihiko ^{[1
]}

Hisaichi, Katsuya ^{[1
]}

Hirai, Keisuke ^{[1
]}

Habashita, Hiromu ^{[1
]}

Takaoka, Yoshikazu ^{[3
]}

Tada, Hideaki ^{[2
]}

Sagawa, Kenji ^{[4
]}

Shibayama, Shiro ^{[2
]}

Maeda, Kenji ^{[5
,6
]}

Mitsuya, Hiroaki ^{[5
,6
]}

Nakai, Hisao ^{[1
]}

Fukushima, Daikichi ^{[2
]}

Toda, Masaaki ^{[1
]}

机构：

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

[2] Ono Pharmaceut Co Ltd, Tsukuba Res Inst, Ibaraki 300424, Japan

[3] Ono Pharmaceut Co Ltd, Fukui Res Inst, Fukui 9138538, Japan

[4] Ono Pharmaceut Co Ltd, Osaka 5410056, Japan

[5] Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan

[6] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 14期

关键词：

CCR5; Chemokine; Anti HIV; HIV-1; ENTRY; CORECEPTOR; COFACTOR; RECEPTOR; POTENT;

D O I：

10.1016/j.bmc.2010.05.057

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：

Using the previously reported novel spirodiketopiperazine scaffold, the design and synthesis of orally available CCR5 antagonists was undertaken. Compounds possessing a carboxylic acid function in the appropriate position showed improved oral exposure (AUC) relative to the initial chemical leads without reduction in the antagonist activity. The optimized compound 40 was found to show potent anti-HIV activity. Full details of structure-activity relationship (SAR) study are presented. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：5208 / 5223

页数：16

共 50 条

[1] Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles
Nishizawa, Rena
Nishiyama, Toshihiko
Hisaichi, Katsuya
Hirai, Keisuke
Habashita, Hiromu
Takaoka, Yoshikazu
Tada, Hideaki
Sagawa, Kenji
Shibayama, Shiro
Maeda, Kenji
Mitsuya, Hiroaki
Nakai, Hisao
Fukushima, Daikichi
Toda, Masaaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2010, 20 (02) : 763 - 766
[2] Spirodiketopiperazine-based CCR5 antagonist: Discovery of an antiretroviral drug candidate
Nishizawa, Rena
Nishiyama, Toshihiko
Hisaichi, Katsuya
Minamoto, Chiaki
Matsunaga, Naoki
Takaoka, Yoshikazu
Nakai, Hisao
Jenkinson, Stephen
Kazmierski, Wieslaw M.
Tada, Hideaki
Sagawa, Kenji
Shibayama, Shiro
Fukushima, Daikichi
Maeda, Kenji
Mitsuya, Hiroaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2011, 21 (04) : 1141 - 1145
[3] Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite
Nishizawa, Rena
Nishiyama, Toshihiko
Hisaichi, Katsuya
Matsunaga, Naoki
Minamoto, Chiaki
Habashitaa, Hiromu
Takaoka, Yoshikazu
Toda, Masaaki
Shibayama, Shiro
Tada, Hideaki
Sagawa, Kenji
Fukushima, Daikichi
Maeda, Kenji
Mitsuya, Hiroaki
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2007, 17 (03) : 727 - 731
[4] Discovery of potent and orally bioavailable CCR5 antagonists: Part I
Wei, Robert G.
Chen, Binglong
Dunning, Laura
Ho, Elena
Jaroch, Stefan
Lee, Wheeseong
Onuffer, James
Subramanyam, Babu
Shen, Jun
Tseng, Jih-Lie
Ye, Bin
Gary, Phillips
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2007, 233 : 596 - 596
[5] Discovery of potent, orally bioavailable CCR5 antagonists - 2.
Palani, A
Shapiro, S
Josien, H
Bara, T
Clader, J
Greenlee, W
Tagat, J
Steensma, R
McCombie, S
Neustadt, B
Pushpavanam, P
Chan, TM
Evans, A
Blythin, D
Ganguly, A
Piwinski, J
Dan, N
Baroudy, B
Endres, M
Strizki, J
Vantuno, N
Cox, K
Broske, L
Zhang, X
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2001, 221 : U5 - U5
[6] Discovery of potent, orally bioavailable CCR5 antagonists - 1.
Tagat, J
Nazareno, D
Vice, S
Lin, S
Steensma, R
Miller, M
Bauer, A
McCombie, S
Palani, A
Josien, H
Clader, J
Neustadt, B
Greenlee, W
Ganguly, A
Piwinski, J
Chan, TM
Evans, A
Dan, N
Baroudy, B
Endres, M
Strizki, J
Vantuno, N
Cox, K
Broske, L
Zhang, X
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2001, 221 : U5 - U5
[7] Orally bioavailable competitive CCR5 antagonists
Thoma, G
Nuninger, F
Schaefer, M
Akyel, KG
Albert, R
Beerli, C
Bruns, C
Francotte, E
Luyten, M
MacKenzie, D
Oberer, L
Streiff, MB
Wagner, T
Walter, H
Weckbecker, G
Zerwes, HG
JOURNAL OF MEDICINAL CHEMISTRY, 2004, 47 (08) : 1939 - 1955
[8] The discovery of a novel orally available CCR5 antagonist, as a therapeutic for HIV-1 infection
Nogi, Rena Nishizawa
Nishiyama, Toshihiko
Hisaichi, Katsuya
Minamoto, Chiaki
Matsunaga, Naoki
Hirai, Keisuke
Habashita, Hiromu
Takaoka, Yoshikazu
Toda, Masaaki
Takahashi, Eiji
Imawaka, Haruo
Sagawa, Kenji
Shibayama, Shiro
Fukushima, Daikichi
Maeda, Kenji
Mitsuya, Hiroaki
ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY, 2006, 231
[9] The design and discovery of novel amide CCR5 antagonists
Pryde, David C.
Corless, Martin
Fenwick, David R.
Mason, Helen J.
Stammen, Blanda C.
Stephenson, Peter T.
Ellis, David
Bachelor, David
Gordon, David
Barber, Christopher G.
Wood, Anthony
Middleton, Donald S.
Blakemore, David C.
Parsons, Gemma C.
Eastwood, Rachel
Platts, Michelle Y.
Statham, Keith
Paradowski, Kerry A.
Burt, Catherine
Klute, Wolfgang
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2009, 19 (04) : 1084 - 1088
[10] Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-Chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro
Maeda, K
Nakata, H
Koh, Y
Miyakawa, T
Ogata, H
Takaoka, Y
Shibayama, S
Sagawa, K
Fukushima, D
Moravek, J
Koyanagi, Y
Mitsuya, H
JOURNAL OF VIROLOGY, 2004, 78 (16) : 8654 - 8662

← 1 2 3 4 5 →