73736-50-2Relevant articles and documents
Characterization of the active site properties of CYP4F12
Eksterowicz, John,Rock, Dan A.,Rock, Brooke M.,Wienkers, Larry C.,Foti, Robert S.
, p. 1698 - 1707 (2014)
Cytochrome P450 4F12 is a drug-metabolizing enzyme that is primarily expressed in the liver, kidney, colon, small intestine, and heart. The properties of CYP4F12 that may impart an increased catalytic selectivity (decreased promiscuity) were explored through in vitro metabolite elucidation, kinetic isotope effect experiments, and computational modeling of the CYP4F12 active site. By using astemizole as a probe substrate for CYP4F12 and CYP3A4, it was observed that although CYP4F12 favored astemizole O-demethylation as the primary route of metabolism, CYP3A4 was capable of metabolizing astemizole at multiple sites on the molecule. Deuteration of astemizole at the site of O-demethylation resulted in an isotope effect of 7.1 as well as an 8.3-fold decrease in the rate of clearance for astemizole by CYP4F12. Conversely, although an isotope effect of 3.8 was observed for the formation of the O-desmethyl metabolite when deuterated astemizole was metabolized by CYP3A4, there was no decrease in the clearance of astemizole. Development of a homology model of CYP4F12 based on the crystal structure of cytochrome P450 BM3 predicted an active site volume for CYP4F12 that was approximately 76% of the active site volume of CYP3A4. As predicted, multiple favorable binding orientations were available for astemizole docked into the active site of CYP3A4, but only a single binding orientation with the site of O-demethylation oriented toward the heme was identified for CYP4F12. Overall, it appears that although CYP4F12 may be capable of binding similar ligands to other cytochrome P450 enzymes such as CYP3A4, the ability to achieve catalytically favorable orientations may be inherently more difficult because of the increased steric constraints of the CYP4F12 active site. Copyright
Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action
Kumar, Malkeet,Okombo, John,Mambwe, Dickson,Taylor, Dale,Lawrence, Nina,Reader, Janette,Van Der Watt, Mari?tte,Fontinha, Diana,Sanches-Vaz, Margarida,Bezuidenhout, Belinda C.,Lauterbach, Sonja B.,Liebenberg, Dale,Birkholtz, Lyn-Marie,Coetzer, Theresa L.,Prudêncio, Miguel,Egan, Timothy J.,Wittlin, Sergio,Chibale, Kelly
, p. 303 - 315 (2019/01/15)
A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC50s) of 50 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC50: 1-5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.
Radiosynthesis and characterization of astemizole derivatives as lead compounds toward PET imaging of τ-pathology
Riss, Patrick J.,Brichard, Laurent,Ferrari, Valentina,Williamson, David J.,Fryer, Tim D.,Hong, Young T.,Baron, Jean-Claude,Aigbirhio, Franklin I.
supporting information, p. 852 - 855 (2013/08/26)
Formation of neurofibrillary tangles, comprising of microtubule-associated tau protein, is a hallmark of a group of neurodegenerative diseases, including Alzheimer's disease. In consequence, in vivo imaging of neurofibrillary tangles is a current focus of positron emission tomography research. Herein, development of an in vitro radioligand binding assay which uses synthetic aggregates as a model of neurofibrillary tangles is reported, together with evaluation of novel derivatives of the tau protein ligand astemizole. The Royal Society of Chemistry 2013.
