142256-41-5Relevant articles and documents
2-Hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic Acid with Inbuilt β-NHydroxy-γ-keto-Acid pharmacophore as HCV NS5B polymerase inhibitors
Deore,Chen,Chen,Chang,Chuang,Chern,Wang,Chern
, p. 613 - 624 (2012/07/28)
The inbuilt 2-N-hydroxy-1-oxo-3-carboxylic acid of isoquinolone was designed as pyrophosphate mimic for hepatitis C NS5B polymerase. Various 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives 11a-p were synthesized and evaluated as HCV NS5B polymerase inhibitors. Compound 11c exhibited moderate inhibitory potency based on the inorganic pyrophosphate generation (IC50 = 9.5 μM) and based on NTP incorporation by NS5B enzyme (IC50 = 5.9 μM). Compound 11c demonstrated antiviral activity (EC50 = 15.7 μM) and good selectivity in HCV genotype 1b replicon Ava.5 cells. Compound 11c reduced the interaction of NTP to NS5B polymerase. Docking model showed that 11c situated in similar orientation to the bound uridine triphosphate in the active site of NS5B polymerase. As a result, 2-hydroxy-1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid was disclosed as a novel inbuilt β-Nhydroxy-γ-keto-acid pharmacophore for HCV NS5B polymerase inhibitors.
Discovery, synthesis and biological evaluation of isoquinolones as novel and highly selective JNK inhibitors (1)
Asano, Yasutomi,Kitamura, Shuji,Ohra, Taiichi,Aso, Kazuyoshi,Igata, Hideki,Tamura, Tomoko,Kawamoto, Tomohiro,Tanaka, Toshimasa,Sogabe, Satoshi,Matsumoto, Shin-ichi,Yamaguchi, Masashi,Kimura, Hiroyuki,Itoh, Fumio
, p. 4715 - 4732 (2008/09/21)
A novel series of 4-phenylisoquinolones were synthesized and evaluated as c-Jun N-terminal kinase (JNK) inhibitors. Initial modification at the 2- and 3-positions of the isoquinolone ring of hit compound 4, identified from high-throughput screening, led to the lead compound 6b. The optimization was carried out using a JNK1-binding model of 6b and several compounds exhibited potent JNK inhibition. Among them, 11g significantly inhibited cardiac hypertrophy in rat pressure-overload models without affecting blood pressure and the concept of JNK inhibitors as novel therapeutic agents for heart failure was confirmed.
Novel, Potent, and Orally Active Substance P Antagonists: Synthesis and Antagonist Activity of N-Benzylcarboxamide Derivatives of Pyridopyridine
Natsugari, Hideaki,Ikeura, Yoshinori,Kiyota, Yutaka,Ishichi, Yuji,Ishimaru, Takenori,et al.
, p. 3106 - 3120 (2007/10/02)
A series of 4-phenylisoquinolone derivatives were synthesized and evaluated for NK1 (substance P) antagonist activity.Highly potent antagonists, 4-phenyl-3-isoquinolone-N-benzylcarboxamides (11), were discovered from the structure-activity relationship studies on the isoquinolone-urea lead 1a.Optimization of the activity in this series resulted in the development of 5-phenyl-6-pyridopyridine-N-benzylcarboxamides (30) which are highly potent orally active NK1 antagonists.Among the compounds synthesized, N--7,8-dihydro-N,7-dimethyl-8-oxo-5-(substituted phenyl)-6-pyridopyridinecarboxamides (30a,f,g) showed excellent antagonist activities with IC50 values (in vitro inhibition of 125I>BH-SP binding in human IM-9-cells) of 0.21-0.34 nM and ED50 values (in vivo inhibition of capsaicin-induced plasma extravasation in guinea-pig trachea, iv) of 0.017-0.030 mg/kg.These compounds exhibited significantly potent activity upon oral adiministration with ED50 values of 0.068-0.17 mg/kg.Conformational studies on 30g indicated that the two stable conformers of 30g are quite similar to those of CP-99,994.
