Discovery of orally available spirodiketopiperazine-based CCR5 antagonists.
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.
Nishizawa
Rena
R
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan. r.nishizawa@ono.co.jp
Nishiyama
Toshihiko
T
Hisaichi
Katsuya
K
Hirai
Keisuke
K
Habashita
Hiromu
H
Takaoka
Yoshikazu
Y
Tada
Hideaki
H
Sagawa
Kenji
K
Shibayama
Shiro
S
Maeda
Kenji
K
Mitsuya
Hiroaki
H
Nakai
Hisao
H
Fukushima
Daikichi
D
Toda
Masaaki
M
D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D018938:Caco-2 Cells; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism
D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010879:Piperazines; D019713:Receptors, CCR5