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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).
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