JianHua Liu
Pfizer
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Publication
Featured researches published by JianHua Liu.
Drug Metabolism and Disposition | 2006
Xingrong Liu; Bill J. Smith; Cuiping Chen; Ernesto Callegari; Stacey L. Becker; Xi Chen; Julie Cianfrogna; Angela C. Doran; Shawn D. Doran; John P. Gibbs; Natilie Hosea; JianHua Liu; Frederick R. Nelson; Mark A. Szewc; Jeffrey Van Deusen
This study was designed to evaluate the use of cerebrospinal fluid (CSF) drug concentration and plasma unbound concentration (Cu,plasma) to predict brain unbound concentration (Cu,brain). The concentration-time profiles in CSF, plasma, and brain of seven model compounds were determined after subcutaneous administration in rats. The Cu,brain was estimated from the product of total brain concentrations and unbound fractions, which were determined using brain tissue slice and brain homogenate methods. For theobromine, theophylline, caffeine, fluoxetine, and propranolol, which represent rapid brain penetration compounds with a simple diffusion mechanism, the ratios of the area under the curve of Cu,brain/CCSF and Cu,brain/Cu,plasma were 0.27 to 1.5 and 0.29 to 2.1, respectively, using the brain slice method, and were 0.27 to 2.9 and 0.36 to 3.9, respectively, using the brain homogenate method. A P-glycoprotein substrate, CP-141938 (methoxy-3-[(2-phenyl-piperadinyl-3-amino)-methyl]-phenyl-N-methyl-methane-sulfonamide), had Cu,brain/CCSF and Cu,brain/Cu,plasma ratios of 0.57 and 0.066, using the brain slice method, and 1.1 and 0.13, using the brain homogenate method, respectively. The slow brain-penetrating compound, N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl-]sarcosine, had Cu,brain/CCSF and Cu,brain/Cu,plasma ratios of 0.94 and 0.12 using the brain slice method and 0.15 and 0.018 using the brain homogenate method, respectively. Therefore, for quick brain penetration with simple diffusion mechanism compounds, CCSF and Cu,plasma represent Cu,brain equally well; for efflux substrates or slow brain penetration compounds, CCSF appears to be equivalent to or more accurate than Cu,plasma to represent Cu,brain. Thus, we hypothesize that CCSF is equivalent to or better than Cu,plasma to predict Cu,brain. This hypothesis is supported by the literature data.
Journal of Medicinal Chemistry | 2012
Michael Aaron Brodney; Gabriela Barreiro; Kevin Ogilvie; Eva Hajos-Korcsok; John C. Murray; Felix Vajdos; Claude Ambroise; Curt Christoffersen; Katherine Fisher; Lorraine Lanyon; JianHua Liu; Charles E. Nolan; Jane M. Withka; Kris A. Borzilleri; Ivan Viktorovich Efremov; Christine E. Oborski; Alison H. Varghese; Brian T. O’Neill
β-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimers disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (HBDs) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogues and the in silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central Aβ(X-40) levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies of the P-gp knockout mouse provided evidence that efflux transporters affected the amount of Aβ lowering versus that observed in wild-type (WT) mouse at an equivalent dose.
Neurodegenerative Diseases | 2013
Yasong Lu; Hugh A. Barton; Louis Leung; Liming Zhang; Eva Hajos-Korcsok; Charles E. Nolan; JianHua Liu; Stacey L. Becker; Kathleen M. Wood; Ashley Robshaw; Christine Taylor; Brian Thomas O'neill; Michael Aaron Brodney; David Riddell
Background: Reducing brain β-amyloid (Aβ) via inhibition of β-secretase, or inhibition/modulation of γ-secretase, has been widely pursued as a potential disease-modifying treatment for Alzheimers disease. Compounds that act through these mechanisms have been screened and characterized with Aβ lowering in the brain and/or cerebrospinal fluid (CSF) as the primary pharmacological end point. Interpretation and translation of the pharmacokinetic (PK)/pharmacodynamic (PD) relationship for these compounds is complicated by the relatively slow Aβ turnover process in these compartments. Objective: To understand Aβ turnover kinetics in preclinical species and humans. Methods: We collected CSF Aβ dynamic data after β- or γ-secretase inhibitor treatment from in-house experiments and the public domain, and analyzed the data using PK/PD modeling to obtain CSF Aβ turnover rates (kout) in the mouse, dog, monkey and human. Results: The kout for CSF Aβ40 follows allometry (kout = 0.395 × body weight-0.351). The kout for CSF Aβ40 is approximately 2-fold higher than the turnover of CSF in rodents, but in higher species, the two are comparable. Conclusion: The turnover of CSF Aβ40 was systematically examined, for the first time, in multiple species through quantitative modeling of multiple data sets. Our result suggests that the clearance mechanisms for CSF Aβ in rodents may be different from those in the higher species. The understanding of Aβ turnover has considerable implications for the discovery and development of Aβ-lowering therapeutics, as illustrated from the perspectives of preclinical PK/PD characterization and preclinical-to-clinical translation.
Journal of Medicinal Chemistry | 2015
Christopher L. Shaffer; Nandini Chaturbhai Patel; Jacob Bradley Schwarz; Renato J. Scialis; Yunjing Wei; Xinjun J. Hou; Longfei Xie; Kapil Karki; Dianne K. Bryce; Sarah Osgood; William E. Hoffmann; John T. Lazzaro; Cheng Chang; Dina McGinnis; Susan M. Lotarski; JianHua Liu; R. Scott Obach; Mark L. Weber; Laigao Chen; Kenneth Zasadny; Patricia A. Seymour; Christopher J. Schmidt; Mihály Hajós; Raymond S. Hurst; Jayvardhan Pandit; Christopher J. O’Donnell
A unique tetrahydrofuran ether class of highly potent α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiators has been identified using rational and structure-based drug design. An acyclic lead compound, containing an ether-linked isopropylsulfonamide and biphenyl group, was pharmacologically augmented by converting it to a conformationally constrained tetrahydrofuran to improve key interactions with the human GluA2 ligand-binding domain. Subsequent replacement of the distal phenyl motif with 2-cyanothiophene to enhance its potency, selectivity, and metabolic stability afforded N-{(3S,4S)-4-[4-(5-cyano-2-thienyl)phenoxy]tetrahydrofuran-3-yl}propane-2-sulfonamide (PF-04958242, 3), whose preclinical characterization suggests an adequate therapeutic index, aided by low projected human oral pharmacokinetic variability, for clinical studies exploring its ability to attenuate cognitive deficits in patients with schizophrenia.
Alzheimers & Dementia | 2010
Eva Hajos-Korcsok; Charles E. Nolan; Christine E. Oborski; Lorraine Lanyon; Dane Liston; Claude Ambroise; Katherine Fisher; Stephen Noell; Curt Christoffersen; Sarah Grimwood; Divine Hannah; Feng Bian; JianHua Liu; Frederick R. Nelson; Yasong Lu; Heather Anne Coffey; Kevin Ogilvie; Karen Coffman; Ivan Viktorovich Efremov; Christopher John Helal; Michael Aaron Brodney; Brian Thomas O'neill
measures (in vitro-in vivo correlation, IVIVC) and identified the best IVIVC, and (3) analyzed the best IVIVC quantitatively to understand in vitro-in vivo translation. Results: Within the potency range of up to 2500 nM, the WT-WCA and mutant-WCA IC50’s are modestly correlated (R 1⁄4 0.8); both of them are only weakly correlated with EAA IC50 (R < 0.45). The IVIVC inspection found that free brain drug exposure (Cb,u) is more relevant than total brain exposure and that the EAA IC50 best predicts in vivo effect of brain Ab reduction. Further quantitative analyses of the brain Ab-Cb,u/EAA IC50 correlation suggested that the maximum brain Ab reduction under those experimental settings was about 70% and that 50% of reduction from baseline was achieved at Cb,u equivalent to EAA IC50. Conclusions: An IVIVC has been established among brain Ab reduction, free brain drug exposure, and enzyme activity assay IC50. This correlation is instrumental in expediting early discovery of BACE1 inhibitors.
Drug Metabolism and Disposition | 2004
Angela C. Doran; R. Scott Obach; Bill J. Smith; Natilie Hosea; Stacey L. Becker; Ernesto Callegari; Cuiping Chen; Xi Chen; Edna F. Choo; Julie Cianfrogna; Loretta M. Cox; John P. Gibbs; Megan A. Gibbs; Heather L. Hatch; Cornelis E. C. A. Hop; Ilana N. Kasman; Jennifer L. LaPerle; JianHua Liu; Xingrong Liu; Michael Logman; Debra Maclin; Frank M. Nedza; Frederick R. Nelson; Emily R. Olson; Sandhya Rahematpura; David Raunig; Sabrinia Rogers; Kari Schmidt; Douglas K. Spracklin; Mark A. Szewc
Journal of Pharmacology and Experimental Therapeutics | 2005
Xingrong Liu; Bill J. Smith; Cuiping Chen; Ernesto Callegari; Stacey L. Becker; Xi Chen; Julie Cianfrogna; Angela C. Doran; Shawn D. Doran; John P. Gibbs; Natilie Hosea; JianHua Liu; Frederick R. Nelson; Mark A. Szewc; Jeffery Van Deusen
Bioanalysis | 2017
Brendon Kapinos; JianHua Liu; Mary Piotrowski; Julie Keefer; Brian Holder; John S. Janiszewski; Hui Zhang; Matt Troutman
Alzheimers & Dementia | 2013
Charles E. Nolan; Kevin Atchison; Ashley Robshaw; Leslie R. Pustilnik; Stephen Noell; Claude Ambroise; Cathleen Gonzales; Feng Pan; Christine E. Oborski; Eva Hajos-Korcsok; Cheng Chang; Yasong Lu; JianHua Liu; Shawn D. Doran; Andre Negahban; Michael Aaron Brodney; Brian Thomas O'neill; Christopher Ryan Butler; Elizabeth Mary Beck; David Riddell
Alzheimers & Dementia | 2010
Yasong Lu; JianHua Liu; Frederick R. Nelson; Claude Ambroise; Katherine Fisher; Eva Hajos-Korcsok; Stephen Noell; Charles E. Nolan; Christine E. Oborski; Lorraine Lanyon; Curt Christoffersen; Divine Hannah; Ivan Viktorovich Efremov; Chris Helal; Michael Aaron Brodney; Brian Thomas O'neill