Literature DB >> 21256008

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

Rena Nishizawa1, 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.   

Abstract

Following the discovery that hydroxylated derivative 3 (Fig. 1) was one of the oxidative metabolites of the original lead 1, it was found that hydroxylated compound 4 possesses higher in vitro anti-HIV potency than the corresponding non-hydroxylated compound 2. Structural hybridation of 4 with the orally available analog 5 resulted in another orally-available spirodiketopiperazine CCR5 antagonist 6a that possesses more favorable pharmaceutical profile for use as a drug candidate.
Copyright © 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 21256008      PMCID： PMC7597670          DOI： 10.1016/j.bmcl.2010.12.109

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  17 in total

1.  Development of a novel high-throughput surrogate assay to measure HIV envelope/CCR5/CD4-mediated viral/cell fusion using BacMam baculovirus technology.

Authors:  Stephen Jenkinson; David C McCoy; Sandy A Kerner; Robert G Ferris; Wendell K Lawrence; William C Clay; J Patrick Condreay; Chari D Smith
Journal:  J Biomol Screen       Date:  2003-08

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.  The discovery of the CCR5 receptor antagonist, UK-427,857, a new agent for the treatment of HIV infection and AIDS.

Authors:  Anthony Wood; Duncan Armour
Journal:  Prog Med Chem       Date:  2005

4.  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

5.  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 6.  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

7.  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

8.  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

9.  Syntheses and SAR studies of 4-(heteroarylpiperdin-1-yl-methyl)-pyrrolidin-1-yl-acetic acid antagonists of the human CCR5 chemokine receptor.

Authors:  K Shankaran; Karla L Donnelly; Shrenik K Shah; Ravindra N Guthikonda; Malcolm MacCoss; Sander G Mills; Sandra L Gould; Lorraine Malkowitz; Salvatore J Siciliano; Martin S Springer; Anthony Carella; Gwen Carver; Daria Hazuda; Karen Holmes; Joseph Kessler; Janet Lineberger; Michael D Miller; Emilio A Emini; William A Schleif
Journal:  Bioorg Med Chem Lett       Date:  2004-07-05       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.  Real time monitoring of membrane GPCR reconstitution by plasmon waveguide resonance: on the role of lipids.

Authors:  Pierre Calmet; Monica De Maria; Etienne Harté; Daniel Lamb; Maria Serrano-Vega; Ali Jazayeri; Nuska Tschammer; Isabel D Alves
Journal:  Sci Rep       Date:  2016-11-08       Impact factor: 4.379
  2 in total

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