The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme.
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Rational Design, Synthesis, and Structure-Activity Relationship of a Novel Isoquinolinone-Based Series of HBV Capsid Assembly Modulators Leading to the Identification of Clinical Candidate AB-836.
J Med Chem
September 2024
Arbutus Biopharma, Inc., 701 Veterans Circle, Warminster, Pennsylvania 18974, United States.
Inhibition of Hepatitis B Virus (HBV) replication by small molecules that modulate capsid assembly and the encapsidation of pgRNA and viral polymerase by HBV core protein is a clinically validated approach toward the development of new antivirals. Through definition of a minimal pharmacophore, a series of isoquinolinone-based capsid assembly modulators (CAMs) was identified. Structural biology analysis revealed that lead molecules possess a unique binding mode, exploiting electrostatic interactions with accessible phenylalanine and tyrosine residues.
View Article and Find Full Text PDFSynthesis of isoquinolinone-based tricycles as novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors.
Bioorg Med Chem Lett
June 2014
Department of Medicinal Chemistry, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, PR China. Electronic address:
The isoquinolinone-based tricyclic compounds were designed and synthesized. Preliminary biological study of these compounds provided potent compounds 17a, 33b, 33c, 33d, and 33g with low nanomolar IC50s against PARP-1 enzyme.
View Article and Find Full Text PDFPharmacokinetics, oral bioavailability and metabolism of a novel isoquinolinone-based melatonin receptor agonist in rats.
Xenobiotica
November 2012
Division of Life Sciences, and Biotechnology Research Institute, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China.
7-Methoxy-6-(3-methoxy-benzyloxy)-2-methylisoquinolin-1(2H)-one (named as IS0042) is a newly identified melatoninergic agonist which exhibits selectivity to the type 2 melatonin receptor. Here, we examined the in vitro and in vivo pharmacokinetics properties of IS0042 in rats. IS0042 was considerably lipophilic with a modest aqueous solubility of 27.
View Article and Find Full Text PDFSynthesis of isoquinolinone-based tetracycles as poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors.
Bioorg Med Chem
November 2009
Department of Biological Science, Sookmyung Women's University, Seoul, Republic of Korea.
The isoquinolinone-based tetracyclic compounds were designed and synthesized and their PARP-1 inhibitory activity was evaluated. Most of synthesized compounds showed fairly good activity. Also the most active compound 6 showed its activity on potentiation of anticancer agents, temozolamide and etoposide, by 1.
View Article and Find Full Text PDFNon-peptide glycoprotein IIb/IIIa antagonists. 11. Design and in vivo evaluation of 3,4-dihydro-1 (1H)-isoquinolinone-based antagonists and ethyl ester prodrugs.
J Med Chem
November 1996
Merck Research Laboratories, West Point, Pennsylvania 19486, USA.
The structure-activity relationship of a series of orally active glycoprotein IIb/IIIa antagonists containing a nitrogen heterocycle grafted onto a 3,4-dihydro-1 (1H)-isoquinolinone core is described. These compounds are structurally novel analogs of the progenitor compound 1 (L-734,217,[[3(R)-[2-(piperidin-4-yl)ethyl]-2-oxopiperidinyl ]acetyl]-3(R)- methyl-beta-alanine) in which the lactam chiral center has been removed. The 4-piperazinyl- and 4-piperidinyl-substituted 3,4-dihydro-1(1H)-isoquinolinones were found to be optimal for in vitro potency.
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