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. 2010 Jan 15;20(2):763-6.
doi: 10.1016/j.bmcl.2009.11.018. Epub 2009 Nov 12.

Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles

Rena Nishizawa  1 , 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
Affiliations

Spirodiketopiperazine-based CCR5 antagonists: Improvement of their pharmacokinetic profiles

Rena Nishizawa et al. Bioorg Med Chem Lett. .

Abstract

Spirodiketopiperazine-based CCR5 antagonists, showing improved pharmacokinetic profiles without reduction in antagonist activity, were designed and synthesized. We also demonstrate the anti-HIV activity of a representative compound 12, as measured in a p24 assay.

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Figures

Figure 1.
Figure 1.
Discovery of an orally active chemical lead.
Scheme 1.
Scheme 1.
Typical synthetic route of spirodiketopiperazines. Reagents and conditions: (a) MeOH, 55 °C; (b) concd HCl, 55 °C; (c) AcOH, toluene, 80 °C; (d) H2, Pd(OH)2/C, EtOH, 55 °C then 4 N HCl/AcOEt (60–70% in four steps); (e) Ar-CHO, NaBH(OAc)3, AcOH, DMF, then 4 N HCl/AcOEt (50–90%).
Scheme 2.
Scheme 2.
Synthesis of 5a. Reagents and conditions: (a) polystyrene-supported tosylchloride, pyridine, CH2Cl2; (b) 14, iPr2NEt, MeCN, then 4 N HCl/AcOEt (48% in two steps).
See this image and copyright information in PMC

References

    1. Schwarz MK; Wells TNC Nat. Rev. Drug Disc 2002, 1, 347; - PubMed
    2. Gerard C; Rollins BJ Nat. Immunol 2001, 2, 108. - PubMed
    1. Feng Y; Broder CC; Kennedy PE; Berger EA Science 1996, 272, 872; - PubMed
    2. Deng HK; Liu R; Ellmeier W; Choe S; Unutmaz D; Burkhart M; Marzio PD; Marmon S; Sutton RE; Hill CM; Davis CB; Peiper SC; Schall TJ; Littman DR; Landau NR Nature 1996, 381, 661; - PubMed
    3. Dragic T; Litwin V; Allaway GP; Martin SR; Huang Y; Nagashima KA; Cayanan C; Maddon PJ; Koup RA; Moore JP; Paxton WA Nature 1996, 381, 667; - PubMed
    4. Alkhatib G; Combadiere C; Broder CC; Feng Y; Kennedy PE; Murphy PM; Berger EA Science 1996, 272, 1955; - PubMed
    5. Berger EA; Murphy PM; Farber JM Annu. Rev. Immunol 1999, 17, 657; - PubMed
    6. Caldwell DJ; Evans JD Exp. Opin. Pharmacother 2008, 9, 3231. - PubMed
    1. Hoffmann C; Mulcahy F Overview of Antiretroviral Agents In HIV Medicine 2006; Hoffmann C, Rockstroh JK, Kamps BS, Eds.; Flying: Paris, 2006; p 94 FlyingPublisher.com.
    1. Leonard JT; Roy K Curr. Med. Chem 2006, 13, 91. - PubMed
    1. Habashita H; Kokubo M; Hamano S; Hamanaka N; Toda M; Shibayama S; Tada H; Sagawa K; Fukushima D; Maeda K; Mitsuya HJ Med. Chem 2006, 49, 4140; - PubMed
    2. Nishizawa R; Nishiyama T; Hisaichi K; Matsunaga N; Minamoto C; Habashita H; Takaoka Y; Toda M; Shibayama S; Tada H; Sagawa K; Fukushima D; Maeda K; Mitsuya H Bioorg. Med. Chem. Lett 2007, 17, 727. - PubMed

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