501698-49-3Relevant academic research and scientific papers
Systematic investigation of halogen bonding in protein-ligand interactions
Hardegger, Leo A.,Kuhn, Bernd,Spinnler, Beat,Anselm, Lilli,Ecabert, Robert,Stihle, Martine,Gsell, Bernard,Thoma, Ralf,Diez, Joachim,Benz, Joerg,Plancher, Jean-Marc,Hartmann, Guido,Banner, David W.,Haap, Wolfgang,Diederich, Francois
, p. 314 - 318 (2011)
Halogen bonding triggers activity: Increasing binding affinity was observed for a series of covalent human Cathepsin L inhibitors by exchanging an aryl ring H atom with Cl, Br, and I, which undergo halogen bonding with the C=O group of Gly61 in the S3 pocket of the enzyme. Fluorine, in contrast, strongly avoids halogen bonding (see scheme). The strong distance and angle dependence of halogen bonding was confirmed for biological systems. Copyright
AMINO ARYL ACETAMIDES AND THEIR USE IN THE TREATMENT OF MALARIA
-
Page/Page column 39, (2011/06/19)
Amino phenyl acetamide compounds of Formula (I):and pharmaceutically acceptable salts thereof: wherein R1, R2, R3 and Ra are as defined in the description, use of such compounds in the chemotherapy of certain parasitic protozoal infections such as malaria, pharmaceutical compositions including such compounds and processes for the preparation of such compounds, are provided.
Cyclopropyl carboxamides: A new oral antimalarial series derived from the Tres Cantos Anti-Malarial Set (TCAMS)
Rueda, Lourdes,Castellote, Isabel,Castro-Pichel, Julia,Chaparro, Maria J.,De La Rosa, Juan Carlos,Garcia-Perez, Adolfo,Gordo, Mariola,Jimenez-Diaz, Maria Belen,Kessler, Albane,MacDonald, Simon J.F.,Martinez, Maria Santos,Sanz, Laura M.,Gamo, Francisco Javier,Fernandez, Esther
supporting information; experimental part, p. 840 - 844 (2012/01/05)
Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.
Discovery of 2-[1-(4-Chlorophenyl)cyclopropyl]-3-hydroxy-8- (trifluoromethyl)quinoline-4-carboxylic acid (PSI-421), a P-selectin inhibitor with improved pharmacokinetic properties and oral efficacy in models of vascular injury
Huang, Adrian,Moretto, Alessandro,Janz, Kristin,Lowe, Michael,Bedard, Patricia W.,Tam, Steve,Di, Li,Clerin, Valerie,Sushkova, Natalia,Tchernychev, Boris,Tsao, Desiree H. H.,Keith Jr., James C.,Shaw, Gray D.,Schaub, Robert G.,Wang, Qin,Kaila, Neelu
supporting information; experimental part, p. 6003 - 6017 (2010/11/19)
Previously, we reported the discovery of PSI-697 (1a), a C-2 benzyl substituted quinoline salicylic acid-based P-selectin inhibitor. It is active in a variety of animal models of cardiovascular disease. Compound 1a has also been shown to be well tolerated and safe in healthy volunteers at doses of up to 1200 mg in a phase 1 single ascending dose study. However, its oral bioavailability was low. Our goal was to identify a back up compound with equal potency, increased solubility, and increased exposure. We expanded our structure-activity studies in this series by branching at the α position of the C-2 benzyl side chain and through modification of substituents on the carboxylic A-ring of the quinoline. This resulted in discovery of PSI-421 with marked improvement in aqueous solubility and pharmacokinetic properties. This compound has shown oral efficacy in animal models of arterial and venous injury and was selected as a preclinical development compound for potential treatment of such diseases as atherosclerosis and deep vein thrombosis.
