52573-74-7Relevant articles and documents
5-Aminothiophene-2,4-dicarboxamide analogues as hepatitis B virus capsid assembly effectors
Tang, Jing,Huber, Andrew D.,Pineda, Dallas L.,Boschert, Kelsey N.,Wolf, Jennifer J.,Kankanala, Jayakanth,Xie, Jiashu,Sarafianos, Stefan G.,Wang, Zhengqiang
supporting information, p. 179 - 192 (2019/01/04)
Chronic hepatitis B virus (HBV) infection represents a major health threat. Current FDA-approved drugs do not cure HBV. Targeting HBV core protein (Cp) provides an attractive approach toward HBV inhibition and possibly infection cure. We have previously identified and characterized a 5-amino-3-methylthiophene-2,4-dicarboxamide (ATDC) compound as a structurally novel hit for capsid assembly effectors (CAEs). We report herein hit validation through studies on absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK), and hit optimization via analogue synthesis aiming to probe the structure-activity relationship (SAR) and structure-property relationship (SPR). In the end, these medicinal chemistry efforts led to the identification of multiple analogues strongly binding to Cp, potently inhibiting HBV replication in nanomolar range without cytotoxicity, and exhibiting good oral bioavailability (F). Two of our analogues, 19o (EC50 = 0.11 μM, CC50 > 100 μM, F = 25%) and 19k (EC50 = 0.31 μM, CC50 > 100 μM, F = 46%), displayed overall lead profiles superior to reported CAEs 7–10 used in our studies.
Development and SAR of functionally selective allosteric modulators of GABAA receptors
Alhambra, Cristobal,Becker, Chris,Blake, Timothy,Chang, Amy,Damewood Jr., James R.,Daniels, Thalia,Dembofsky, Bruce T.,Gurley, David A.,Hall, James E.,Herzog, Keith J.,Horchler, Carey L.,Ohnmacht, Cyrus J.,Schmiesing, Richard Jon,Dudley, Adam,Ribadeneira, Maria D.,Knappenberger, Katherine S.,MacIag, Carla,Stein, Mark M.,Chopra, Maninder,Liu, Xiaodong F.,Christian, Edward P.,Arriza, Jeffrey L.,Chapdelaine, Marc J.
experimental part, p. 2927 - 2938 (2011/06/21)
Positive modulators at the benzodiazepine site of α2- and α3-containing GABAA receptors are believed to be anxiolytic. Through oocyte voltage clamp studies, we have discovered two series of compounds that are positive modulators at α2-/α3-containing GABAA receptors and that show no functional activity at α1-containing GABA A receptors. We report studies to improve this functional selectivity and ultimately deliver clinical candidates. The functional SAR of cinnolines and quinolines that are positive allosteric modulators of the α2- and α3-containing GABAA receptors, while simultaneously neutral antagonists at α1-containing GABAA receptors, is described. Such functionally selective modulators of GABAA receptors are expected to be useful in the treatment of anxiety and other psychiatric illnesses.
A new class of small molecule RNA polymerase inhibitors with activity against Rifampicin-resistant Staphylococcus aureus1
Arhin, Francis,Belanger, Odette,Ciblat, Stephane,Dehbi, Mohammed,Delorme, Daniel,Dietrich, Evelyne,Dixit, Dilip,Lafontaine, Yanick,Lehoux, Dario,Liu, Jing,McKay, Geoffrey A.,Moeck, Greg,Reddy, Ranga,Rose, Yannick,Srikumar, Ramakrishnan,Tanaka, Kelly S.E.,Williams, Daniel M.,Gros, Philippe,Pelletier, Jerry,Parr Jr., Thomas R.,Far, Adel Rafai
, p. 5812 - 5832 (2007/10/03)
The RNA polymerase holoenzyme is a proven target for antibacterial agents. A high-throughput screening program based on this enzyme from Staphylococcus aureus had previously identified a 2-ureidothiophene-3-carboxylate as a low micromolar inhibitor. An investigation of the relationships between the structures of this class of compounds and their inhibitory- and antibacterial activities is described here, leading to a set of potent RNA polymerase inhibitors with antibacterial activity. Characterization of this bioactivity, including studies of the mechanism of action, is provided, highlighting the power of the reverse chemical genetics approach in providing tools to inhibit the bacterial RNA polymerase.
