Literature DB >> 20542438

Discovery of orally available spirodiketopiperazine-based CCR5 antagonists.

Rena Nishizawa1, Toshihiko Nishiyama, Katsuya Hisaichi, Keisuke Hirai, Hiromu Habashita, Yoshikazu Takaoka, Hideaki Tada, Kenji Sagawa, Shiro Shibayama, Kenji Maeda, Hiroaki Mitsuya, Hisao Nakai, Daikichi Fukushima, Masaaki Toda.   

Abstract

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. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 20542438      PMCID： PMC7566811          DOI： 10.1016/j.bmc.2010.05.057

Source DB:  PubMed          Journal:  Bioorg Med Chem        ISSN： 0968-0896            Impact factor:   3.641


  16 in total

Review 1.  New therapeutics that modulate chemokine networks.

Authors:  Matthias K Schwarz; Timothy N C Wells
Journal:  Nat Rev Drug Discov       Date:  2002-05       Impact factor: 84.694

2.  Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite.

Authors:  Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Naoki Matsunaga; Chiaki Minamoto; Hiromu Habashita; Yoshikazu Takaoka; Masaaki Toda; Shiro Shibayama; Hideaki Tada; Kenji Sagawa; Daikichi Fukushima; Kenji Maeda; Hiroaki Mitsuya
Journal:  Bioorg Med Chem Lett       Date:  2006-11-01       Impact factor: 2.823

Review 3.  A comprehensive listing of bioactivation pathways of organic functional groups.

Authors:  Amit S Kalgutkar; Iain Gardner; R Scott Obach; Christopher L Shaffer; Ernesto Callegari; Kirk R Henne; Abdul E Mutlib; Deepak K Dalvie; Jae S Lee; Yasuhiro Nakai; John P O'Donnell; Jason Boer; Shawn P Harriman
Journal:  Curr Drug Metab       Date:  2005-06       Impact factor: 3.731

4.  Chloro-substituted 3-alkylamino-4H-1,2,4-benzothiadiazine 1,1-dioxides as ATP-sensitive potassium channel activators: impact of the position of the chlorine atom on the aromatic ring on activity and tissue selectivity.

Authors:  Bernard Pirotte; Pascal de Tullio; Quynh-Anh Nguyen; Fabian Somers; Pierre Fraikin; Xavier Florence; Philip Wahl; John Bondo Hansen; Philippe Lebrun
Journal:  J Med Chem       Date:  2010-01-14       Impact factor: 7.446

5.  Identification of a major co-receptor for primary isolates of HIV-1.

Authors:  H Deng; R Liu; W Ellmeier; S Choe; D Unutmaz; M Burkhart; P Di Marzio; S Marmon; R E Sutton; C M Hill; C B Davis; S C Peiper; T J Schall; D R Littman; N R Landau
Journal:  Nature       Date:  1996-06-20       Impact factor: 49.962

6.  CC CKR5: a RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for macrophage-tropic HIV-1.

Authors:  G Alkhatib; C Combadiere; C C Broder; Y Feng; P E Kennedy; P M Murphy; E A Berger
Journal:  Science       Date:  1996-06-28       Impact factor: 47.728

Review 7.  Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.

Authors:  E A Berger; P M Murphy; J M Farber
Journal:  Annu Rev Immunol       Date:  1999       Impact factor: 28.527

8.  Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists.

Authors:  Hiromu Habashita; Masaya Kokubo; Shin-ichi Hamano; Nobuyuki Hamanaka; Masaaki Toda; Shiro Shibayama; Hideaki Tada; Kenji Sagawa; Daikichi Fukushima; Kenji Maeda; Hiroaki Mitsuya
Journal:  J Med Chem       Date:  2006-07-13       Impact factor: 7.446

9.  Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles.

Authors:  Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Keisuke Hirai; Hiromu Habashita; Yoshikazu Takaoka; Hideaki Tada; Kenji Sagawa; Shiro Shibayama; Kenji Maeda; Hiroaki Mitsuya; Hisao Nakai; Daikichi Fukushima; Masaaki Toda
Journal:  Bioorg Med Chem Lett       Date:  2009-11-12       Impact factor: 2.823

10.  Spirodiketopiperazine-based CCR5 inhibitor which preserves CC-chemokine/CCR5 interactions and exerts potent activity against R5 human immunodeficiency virus type 1 in vitro.

Authors:  Kenji Maeda; Hirotomo Nakata; Yasuhiro Koh; Toshikazu Miyakawa; Hiromi Ogata; Yoshikazu Takaoka; Shiro Shibayama; Kenji Sagawa; Daikichi Fukushima; Joseph Moravek; Yoshio Koyanagi; Hiroaki Mitsuya
Journal:  J Virol       Date:  2004-08       Impact factor: 5.103
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  2 in total

1.  Discovery of 4-[4-({(3R)-1-butyl-3-[(R)-cyclohexyl(hydroxy)methyl]-2,5-dioxo-1,4,9-triazaspiro[5.5]undec-9-yl}methyl)phenoxy]benzoic acid hydrochloride: a highly potent orally available CCR5 selective antagonist.

Authors:  Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Chiaki Minamoto; Masayuki Murota; Yoshikazu Takaoka; Hisao Nakai; Hideaki Tada; Kenji Sagawa; Shiro Shibayama; Daikichi Fukushima; Kenji Maeda; Hiroaki Mitsuya
Journal:  Bioorg Med Chem       Date:  2011-05-20       Impact factor: 3.641

2.  Spirodiketopiperazine-based CCR5 antagonist: discovery of an antiretroviral drug candidate.

Authors:  Rena Nishizawa; Toshihiko Nishiyama; Katsuya Hisaichi; Chiaki Minamoto; Naoki Matsunaga; Yoshikazu Takaoka; Hisao Nakai; Stephen Jenkinson; Wieslaw M Kazmierski; Hideaki Tada; Kenji Sagawa; Shiro Shibayama; Daikichi Fukushima; Kenji Maeda; Hiroaki Mitsuya
Journal:  Bioorg Med Chem Lett       Date:  2010-12-28       Impact factor: 2.823
  2 in total

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