Journal ArticleDOI
In vitro metabolism of α7 neuronal nicotinic receptor agonist AZD0328 and enzyme identification for its N-oxide metabolite
Diansong Zhou,Minli Zhang,Xiaomei Ye,Chungang Gu,Timothy Piser,Bernard A Lanoue,Sara A Schock,Yi-Fang Cheng,Scott W. Grimm +8 more
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TLDR
The potential for AZD0328 to be inhibited clinically by co-administered drugs or genetic polymorphism is relative low, and the N-oxidation metabolite was the only metabolite detected in human hepatocyte incubations, and it also appeared to be the major in vitro metabolic pathway in a number of preclinical species.Abstract:
1. AZD0328 was pharmacologically characterized as a α7 neuronal nicotinic receptor agonist intended for treatment of Alzheimer's disease. In vitro AZD0328 cross species metabolite profile and enzyme identification for its N-oxide metabolite were evaluated in this study. 2. AZD0328 was very stable in the human hepatocyte incubation, whereas extensively metabolized in rat, dog and guinea pig hepatocyte incubations. The N-oxidation metabolite (M6) was the only metabolite detected in human hepatocyte incubations, and it also appeared to be the major in vitro metabolic pathway in a number of preclinical species. In addition, N-glucuronide metabolite of AZD0328 was observed in human liver microsomes. 3. Other metabolic pathways in the preclinical species include hydroxylation in azabicyclo octane or furopyridine part of the molecule. Pyridine N-methylation of AZD0328 (M2) was identified as a dog specific metabolite, not observed in human or other preclinical species. 4. Multiple enzymes including CYP2D6, CYP3A4/5, FMO1 and FMO3 catalyzed AZD0328 metabolism. The potential for AZD0328 to be inhibited clinically by co-administered drugs or genetic polymorphism is relative low.read more
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The current agonists and positive allosteric modulators of α 7 nAChR for CNS indications in clinical trials
TL;DR: Recent progress made in understanding the role of the α7 nAChR in multiple neuropsychiatric disorders and the pharmacological effects of α7 gated Ca2+-permeable ion channel modulators used in clinical trials are outlined.
Journal ArticleDOI
Metabolism and Pharmacokinetics of Novel Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitor Apatinib in Humans
Jue-Fang Ding,Xiaoyan Chen,Zhiwei Gao,Xiaojian Dai,Liang Li,Cen Xie,Haoyuan Jiang,Lijia Zhang,Dafang Zhong +8 more
TL;DR: Apatinib was a major contributor to the overall pharmacological activity in humans and the enzymes responsible for its metabolism were identified.
Journal ArticleDOI
Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans
Yoshinobu Nakamaru,Yoshiharu Hayashi,Ruriko Ikegawa,Shuji Kinoshita,Begonya Perez Madera,Dave Gunput,Atsuhiro Kawaguchi,Martin Davies,Stuart Mair,Hiroshi Yamazaki,Toshiyuki Kume,Masayuki Suzuki +11 more
TL;DR: This study indicates the involvement of renal excretion and multiple metabolic pathways in the elimination of teneligliptin from the human body, which is unlikely to cause conspicuous drug interactions or changes in its pharmacokinetics patients with renal or hepatic impairment, due to a balance in the eliminated pathways.
Journal ArticleDOI
Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human livers
TL;DR: The results suggest that genetic polymorphism in the human FMO3 gene may lead to changes of drug interactions for N- or S-oxygenations of xenobiotics and endogenous substances and that a probe battery system of benzydamine N- Oxygenation and sulindac sulfide S- oxygengenation activities is recommended to clarify the drug interactions mediated by F MO3.
Journal ArticleDOI
Synthesis of three alpha 7 agonists in labeled form
Charles S. Elmore,Scott W. Landvatter,Peter N. Dorff,Mark E. Powell,David A. Killick,Timothy Blake,James E. Hall,J. Richard Heys,John R. Harding,Rebecca Urbanek,Glen Ernst +10 more
TL;DR: In support of a program to develop an alpha 7 agonist as a treatment for Alzheimer's disease, three drug candidates, 1, 2, and 3, were prepared in labeled forms.
References
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Journal ArticleDOI
Forecasting the global burden of Alzheimer’s disease
TL;DR: The goal was to forecast the global burden of Alzheimer's disease and evaluate the potential impact of interventions that delay disease onset or progression.
Journal Article
Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes.
TL;DR: In the projection of human clearance values, basic and neutral compounds were well predicted when all binding considerations (blood and microsome) were disregarded, however, including both binding considerations also yielded reasonable predictions.
Journal ArticleDOI
Nicotinic effects on cognitive function : behavioral characterization, pharmacological specification, and anatomic localization
TL;DR: Discovery of the behavioral, pharmacological, and anatomic specificity of Nicotinic effects on learning, memory, and attention not only aids the understanding of nicotinic involvement in the basis of cognitive function, but also helps in the development of novelNicotinic treatments for cognitive dysfunction.
Journal ArticleDOI
The conduct of in vitro and in vivo drug-drug interaction studies: A Pharmaceutical Research and Manufacturers of America (PhRMA) perspective
Thorir D. Bjornsson,J. T. Callaghan,Heidi J. Einolf,Volker Fischer,Lawrence Gan,Scott W. Grimm,John Kao,S. Peter King,Gerald T. Miwa,Lan Ni,Gondi N. Kumar,James F. McLeod,R. Scott Obach,Stanley Roberts,Amy L. Roe,Anita Shah,Fred Snikeris,John T. Sullivan,Donald J. Tweedie,José M. Vega,John S Walsh,Steven A. Wrighton +21 more
TL;DR: The intent is to define a minimal best practice for in vitro and in vivo pharmacokinetic drug-drug interaction studies targeted to development (not discovery support) and to defined a data package that can be expected by regulatory agencies in compound registration dossiers.
Journal ArticleDOI
Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system
TL;DR: Recent advances in the understanding of the assembly, activity and conformational transitions of nicotinic receptors are described, as well as developments in the therapeutic application of Nicotinic receptor ligands, with the aim of aiding novel drug discovery by bridging the gap between these two rapidly developing fields.