Field-based affinity optimization of a novel azabicyclohexane scaffold HIV-1 entry inhibitor
Small-molecule HIV-1 entry inhibitors are an extremely attractive therapeutic modality. We have previously demonstrated that the entry inhibitor class can be optimized by using computational means to identify and extend the chemotypes available. Here we demonstrate unique and differential effects of previously published antiviral compounds on the gross structure of the HIV-1 Env complex, with an azabicyclohexane scaffolded inhibitor having a positive effect on glycoprotein thermostability. We demonstrate that modification of the methyltriazole-azaindole headgroup of these entry inhibitors directly effects the potency of the compounds, and substitution of the methyltriazole with an amine-oxadiazole increases the affinity of the compound 1000-fold over parental by improving the on-rate kinetic parameter. These findings support the continuing exploration of compounds that shift the conformational equilibrium of HIV-1 Env as a novel strategy to improve future inhibitor and vaccine design efforts.
Meuser, Megan E.,Rashad, Adel A.,Ozorowski, Gabriel,Dick, Alexej,Ward, Andrew B.,Cocklin, Simon
(2019/05/01)
Rapid synthesis of diversely functionalized 3,4,7-trisubstituted indoles
Synthetic approaches are described for the synthesis of 4-alkoxyindole-7-carboxamides and 4-alkoxy-3-cyanoindole-7-carboxamides, which are useful intermediates in medicinal chemistry research. Two strategies were employed, highlighted by a Bartoli indole synthesis or a sequential and regioselective use of chlorosulfonyl isocyanate to install both the 3-cyano and 7-carboxamido groups. These routes are scalable and afford diversely functionalized indoles for further elaboration.
Grant, Seth W.,Gallagher, Timothy F.,Bobko, Mark A.,Duquenne, Celine,Axten, Jeffrey M.
scheme or table
p. 3376 - 3378
(2011/06/28)
Methods and compounds for treating proliferative diseases
The compounds disclosed herein are indolocarbazoles of Formula (I), which are potent CDK4 inhibitors, and are useful in the treatment of cell proliferative disorders, including cancer. Formula (I).
-
(2008/06/13)
A focused compound library of novel N-(7-indolyl)benzenesulfonamides for the discovery of potent cell cycle inhibitors
A series of compounds containing an N-(7-indolyl)benzenesulfonamide pharmacophore was synthesized and evaluated as a potential antitumor agent. Cell cycle analysis with P388 murine leukemia cells revealed that there were two different classes of potent cell cycle inhibitors; one disrupted mitosis and the other caused G1 accumulation. Herein described is the SAR summary of the substituent patterns on this pharmacophore template. (C) 2000 Elsevier Science Ltd. All rights reserved.