Zhili Xin
Biogen Idec
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Publication
Featured researches published by Zhili Xin.
Journal of Organic Chemistry | 2012
Xianglin Shi; Dominique Hebrault; Michael J. Humora; William F. Kiesman; Hairuo Peng; Tina Talreja; Zezhou Wang; Zhili Xin
Mild reaction conditions for Petasis reactions of substituted salicylaldehydes with various amines and arylboronic acids in the presence of molecular sieves were developed. Molecular sieves (MS) significantly accelerated the reaction rates and drove the reactions to high conversions. The conditions were applied to the synthesis of the core structure of BIIB042, a γ-secretase modulator, without stereochemical erosion of a stereogenic center in the salicylaldehyde intermediate.
ACS Medicinal Chemistry Letters | 2011
Hairuo Peng; Tina Talreja; Zhili Xin; J. Hernan Cuervo; Gnanasambandam Kumaravel; Michael J. Humora; Lin Xu; Ellen Rohde; Lawrence Gan; Mi-young Jung; Melanie Shackett; Sowmya Chollate; Anthone W. Dunah; Pamela A. Snodgrass-Belt; H. Moore Arnold; Arthur G. Taveras; Kenneth J. Rhodes; Robert H. Scannevin
We have investigated a novel series of acid-derived γ-secretase modulators as a potential treatment of Alzheimers disease. Optimization based on cellular potency and brain pharmacodynamics after oral dosing led to the discovery of 10a (BIIB042). Compound 10a is a potent γ-secretase modulator, which lowered Aβ42, increased Aβ38, but had little to no effect on Aβ40 levels both in vitro and in vivo. In addition, compound 10a did not affect Notch signaling in our in vitro assessment. Compound 10a demonstrated excellent pharmacokinetic parameters in multiple species. Oral administration of 10a significantly reduced brain Aβ42 levels in CF-1 mice and Fischer rats, as well as plasma Aβ42 levels in cynomolgus monkeys. Compound 10a was selected as a candidate for preclinical safety evaluation.
Journal of Organic Chemistry | 2013
Xianglin Shi; William F. Kiesman; Anna Levina; Zhili Xin
Binaphthol-catalyzed asymmetric Petasis reactions of salicylaldehydes with dibutyl vinylboronates and secondary amines in the presence of 4 Å molecular sieves (MS) afforded products with up to 99% ee in isolated yields of 39-94%. The 99% ee of the product indicated that the reaction by the binaphthol-catalyzed pathway was roughly 500 times faster than the uncatalyzed pathway. NMR experiments ((1)H and (11)B) showed that the amine component played a role in triggering the reaction between the binaphthol catalyst and the vinylboronate in the catalytic reaction sequence. The 4 Å MS enhanced both the rate and enantioselectivity by effective removal of water from the reaction system. A novel rearrangement reaction of the unconjugated allylic amine Petasis reaction product to a conjugated allylic amine was also observed.
Bioorganic & Medicinal Chemistry Letters | 2011
Zhili Xin; Hairuo Peng; Andrew Zhang; Tina Talreja; Gnanasambandam Kumaravel; Lin Xu; Ellen Rohde; Mi-yong Jung; Melanie Shackett; David Kocisko; Sowmya Chollate; Anthone W. Dunah; Pamela A. Snodgrass-Belt; H. Moore Arnold; Arthur G. Taveras; Kenneth Rhodes; Robert H. Scannevin
Starting from literature examples of nonsteroidal anti-inflammatory drugs (NSAIDs)-type carboxylic acid γ-secretase modulators (GSMs) and using a scaffold design approach, we identified 4-aminomethylphenylacetic acid 4 with a desirable γ-secretase modulation profile. Scaffold optimization led to the discovery of a novel chemical series, represented by 6b, having improved brain penetration. Further SAR studies provided analog 6q that exhibited a good pharmacological profile. Oral administration of 6q significantly reduced brain Aβ42 levels in mice and rats.
Bioorganic & Medicinal Chemistry Letters | 2018
Tricia L. May-Dracka; Robert M. Arduini; Andrea Bertolotti-Ciarlet; Govinda Bhisetti; Margot Brickelmaier; Ellen Cahir-McFarland; Istvan Enyedy; Jason D. Fontenot; Thomas Hesson; Kevin Little; Joe Lyssikatos; Douglas Marcotte; Timothy McKee; Paramasivam Murugan; Thomas Patterson; Hairuo Peng; Mia Rushe; Laura Silvian; Kerri Spilker; Ping Wu; Zhili Xin; Linda C. Burkly
Germinal center kinase-like kinase (GLK, also known as MAP4K3) has been hypothesized to have an effect on key cellular activities, including inflammatory responses. GLK is required for activation of protein kinase C-θ (PKCθ) in T cells. Controlling the activity of T helper cell responses could be valuable for the treatment of autoimmune diseases. This approach circumvents previous unsuccessful approaches to target PKCθ directly. The use of structure based drug design, aided by the first crystal structure of GLK, led to the discovery of several inhibitors that demonstrate potent inhibition of GLK biochemically and in relevant cell lines.
Archive | 2010
Hairuo Peng; Julio H. Cuervo; Alexey Ishchenko; Gnanasambandam Kumaravel; Wen-Cherng Lee; Alexey Lugovskoy; Tina Talreja; Arthur G. Taveras; Zhili Xin
Archive | 2013
Hairuo Peng; Zhili Xin; Lihong Sun; Timothy Chan; Gnanasambandam Kumaravel; Arthur G. Taveras
Archive | 2013
Kevin Guckian; Gnanasambandam Kumaravel; Bin Ma; Sha Mi; Hairuo Peng; Zhaohui Shao; Lihong Sun; Arthur G. Taveras; Deping Wang; Zhili Xin; Lei Zhang
Archive | 2013
Kevin Guckian; Gnanasambandam Kumaravel; Bin Ma; Lihong Sun; Zhili Xin; Lei Zhang
Neuropharmacology | 2016
Robert H. Scannevin; Sowmya Chollate; Melanie Brennan; Pamela A. Snodgrass-Belt; Hairuo Peng; Lin Xu; Mi-young Jung; Thierry Bussiere; Mahin Arastu; Tina Talreja; Zhili Xin; Robert Dunstan; Diana Fahrer; Ellen Rohde; Anthone W. Dunah; Joy Wang; Gnanasambandam Kumaravel; Arthur G. Taveras; H. Moore Arnold; Kenneth Rhodes