Synthesis and evaluation of tricyclic derivatives containing a non-aromatic amide as inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1)

  • Bioorg Med Chem Lett. 2010 Apr 1;20(7):2250-3. doi: 10.1016/j.bmcl.2010.02.014.
Chun-Ho Park  1 ,  Kwangwoo Chun ,  Bo-Young Joe ,  Ji-Seon Park ,  Young-Chul Kim ,  Ji-Soo Choi ,  Dong-Kyu Ryu ,  Seong-Ho Koh ,  Goang Won Cho ,  Seung Hyun Kim ,  Myung-Hwa Kim
Affiliations
  • 1. Drug Discovery Laboratory, R&D Center, Jeil Pharmaceutical Co., Ltd. 117-1, Keungok-Ri, Baekam-Myun, Cheoin-Gu, Yongin-City, Kyunggi-Do 449-861, Republic of Korea.
PMID: 20189385 DOI: 10.1016/j.bmcl.2010.02.014
Abstract

Highly potent poly(ADP-ribose)polymerase-1 (PARP-1) inhibitors, including 9-hydroxy-1,2-dihydro-4H-thiopyrano[3,4-c]quinolin-5(6H)-one derivatives with a non-aromatic A-ring, were synthesized. Among the derivatives, 12a showed low nanomolar enzyme and cellular activity (IC(50) = 42 nM, ED(50) = 220 nM) with good water solubility. Further, 12a exhibited microsomal stability in vitro and brain permeability in vivo.