Journal ArticleDOI
Esterase Activities in the Blood, Liver and Intestine of Several Preclinical Species and Humans
TLDR
Substantial species differences in activity of these esterases were observed between the mouse, rat, dog monkey and human, and such species differences must be considered when using these preclinical species to optimize the pharmacokinetic properties of ester compounds intended for human use.Abstract:
Species and tissue differences in the activity of three major classes of esterases, carboxylesterase (CE), butyrylcholinesterase (BChE) and paraoxonase (PON), were studied. Substantial species differences in activity of these esterases were observed between the mouse, rat, dog monkey and human. Such species differences must be considered when using these preclinical species to optimize the pharmacokinetic properties of ester compounds intended for human use.read more
Citations
More filters
Journal ArticleDOI
Species Difference of Esterase Expression and Hydrolase Activity in Plasma
TL;DR: In conclusion, the esterase expression and hydrolyzing pattern of dog plasma were found to be closest to that of human plasma, and should be considered when selecting model animals for preclinical studies.
Journal ArticleDOI
The Development of Highly Potent Inhibitors for Porcupine
Xiaolei Wang,Jesung Moon,Michael E. Dodge,Xinchao Pan,Lishu Zhang,Jordan M. Hanson,Rubina Tuladhar,Zhiqiang Ma,Heping Shi,Noelle S. Williams,James F. Amatruda,Thomas L. Carroll,Lawrence G. Lum,Chuo Chen +13 more
TL;DR: The structure-activity relationship studies and the identification of subnanomolar inhibitors of Porcn inhibitors are described and the effects of IWPs on Wnt-dependent developmental processes, including zebrafish posterior axis formation and kidney tubule formation are reported.
Journal ArticleDOI
Identification of ABX-1431, a Selective Inhibitor of Monoacylglycerol Lipase and Clinical Candidate for Treatment of Neurological Disorders
Justin S. Cisar,Olivia D. Weber,Jason R. Clapper,Jacqueline L. Blankman,Cassandra L. Henry,Gabriel M. Simon,Jessica P. Alexander,Todd K. Jones,R. Alan B. Ezekowitz,Gary P. O'Neill,Cheryl A. Grice +10 more
TL;DR: Activity-based protein profiling experiments verify the exquisite selectivity of 28 for MGLL versus other members of the serine hydrolase class, and report the optimization of hexafluoroisopropyl carbamate-based irreversible inhibitors of MGLL, culminating in a highly potent, selective, and orally available, CNS-penetrant MGLL inhibitor, ABX-1431.
Journal ArticleDOI
Open Source Drug Discovery: Highly Potent Antimalarial Compounds Derived from the Tres Cantos Arylpyrroles.
Alice E. Williamson,Paul M. Ylioja,Murray N. Robertson,Murray N. Robertson,Yevgeniya Antonova-Koch,Vicky M. Avery,Jonathan B. Baell,Harikrishna Batchu,Sanjay Batra,Jeremy N. Burrows,Soumya Bhattacharyya,Félix Calderón,Susan A. Charman,Julie Clark,Benigno Crespo,Matin Dean,Stefan L. Debbert,Michael J. Delves,Adelaide S. M. Dennis,Frederik Deroose,Sandra Duffy,Sabine Fletcher,Guri Giaever,Irene Hallyburton,Francisco-Javier Gamo,Marinella Gebbia,R. Kiplin Guy,Zoe Hungerford,Kiaran Kirk,Maria J. Lafuente-Monasterio,Anna Lee,Stephan Meister,Corey Nislow,John P. Overington,George Papadatos,Luc Patiny,James Pham,Stuart A. Ralph,Andrea Ruecker,Eileen Ryan,Christopher Southan,Kumkum Srivastava,Chris Swain,Matthew J. Tarnowski,Patrick Thomson,Peter Turner,Iain M. Wallace,Timothy N. C. Wells,Karen L. White,Laura White,Paul Willis,Elizabeth A. Winzeler,Sergio Wittlin,Matthew H. Todd +53 more
TL;DR: One chemical subseries was found to exhibit oral activity but contained a labile ester that could not be replaced without loss of activity, and the original hit exhibited remarkable sensitivity to minor structural change.
Journal ArticleDOI
Predicting Drug Extraction in the Human Gut Wall: Assessing Contributions from Drug Metabolizing Enzymes and Transporter Proteins using Preclinical Models
TL;DR: CYP3A is the enzyme that is frequently implicated in human gut metabolism and is the major focus of this review, and a strategy to assess the impact of gut wall metabolism on oral bioavailability during drug discovery and early development phases is presented.