Adrian Hall
Eisai
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Publication
Featured researches published by Adrian Hall.
Progress in Medicinal Chemistry | 2014
Adrian Hall; Toshal Patel
This chapter reviews the current status of γ-secretase modulators, highlighting key compounds by each company involved in the area. The review focuses on the three main chemotypes: acids, imidazoles and related derivatives and natural products. A section on chemical biology and ligand-binding site elucidation studies is also included. The primary source of information is drawn from peer reviewed literature as this permits analysis of PK-PD relationships and subsequent comment. Discussion of the patent literature is included for completeness. From this analysis, the key issues and challenges in the area are highlighted. The review concludes with a summary of the clinical development status and comment on future prospects of the field.
Drug Metabolism and Disposition | 2013
Natalie R. Inoue; Adrian Hall; Weidong George Lai; Eric Trey Williams
Carboxylesterases hydrolyze esters, amides, and thioesters to produce carboxylic acids and resulting alcohols, amines, and thiols, respectively. Uridine 5′-diphosphate- glucuronosyltransferases are colocalized with carboxylesterases and have the potential to further metabolize carboxylic acids to acyl glucuronides, but it is currently unknown if acyl glucuronides, being esters, also interact with carboxylesterases. Objective: This study explores the ability of acyl glucuronides to act as substrates or inhibitors of human carboxylesterases 1 (hCES1) and 2 (hCES2). Methods: The stability of six acyl glucuronides in the presence of hCES1, hCES2, and buffer alone (100 mM potassium phosphate, pH 7.4, 37°C) were investigated. Reversible inhibition of 4-nitrophenyl acetate hydrolysis by the acyl glucuronides was also studied. Diclofenac-β-d-glucuronide was used to explore potential time-dependent inactivation. Results: The chemical stability half-life values for CGP 47292-β-d-glucuronide, diclofenac-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, (S)-naproxen-β-d-glucuronide, ibuprofen-β–d-glucuronide (racemic), clopidogrel-β-d-glucuronide, and valproate-β-d-glucuronide were found to be 0.252, 0.537, 0.996, 1.77, 3.67, 5.02, and 15.2 hours, respectively. Diclofenac-β-d-glucuronide, clopidogrel-β-d-glucuronide, ibuprofen-β-d-glucuronide, (R)-naproxen-β-d-glucuronide, and (S)-naproxen-β-d-glucuronide selectively inhibited hCES1, with Ki values of 4.32 ± 0.47, 24.8 ± 4.2, 355 ± 38, 468 ± 21, 707 ± 64 µM, respectively, but did not significantly inhibit hCES2. Valproate-β-d-glucuronide and CGP 47292-β-d-glucuronide did not inhibit either hCES. Time-dependent inactivation of hCES1 by diclofenac-β-d-glucuronide was not observed. Lastly, both hCES1 and hCES2 were shown not to catalyze the hydrolysis of the acyl glucuronides studied. Conclusion: Drug-drug interaction studies may be warranted for drugs that metabolize to acyl glucuronides due to the potential inhibition of hCESs.
Archive | 2012
Paschalis Dimopoulos; Adrian Hall; Yoichi Kita; Andrew Madin; Nicola Louise Shuker
Archive | 2010
John Mark Ellard; Christopher Neil Farthing; Adrian Hall
Archive | 2010
Jose Luis Castro Pineiro; Adrian Hall; Andrew Madin; Ngoc-Tri Vo
Archive | 2012
Adrian Hall; Christopher Neil Farthing; Pineiro Jose Luis Castro
Archive | 2014
Adrian Hall; Toshal Patel
Archive | 2012
Adrian Hall; Christopher Neil Farthing; Pineiro Jose Luis Castro
Archive | 2012
Adrian Hall; Christopher Neil Farthing; Pineiro Jose Luis Castro
Archive | 2012
Adrian Hall; Christopher Neil Farthing; Pineiro Jose Luis Castro