James Richard Falsey
Amgen
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Publication
Featured researches published by James Richard Falsey.
Organic Letters | 2010
Andreas Reichelt; James Richard Falsey; Robert M. Rzasa; Oliver R. Thiel; Michal M. Achmatowicz; Robert D. Larsen; Dawei Zhang
An efficient and convenient method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines was exemplified by the synthesis of 20 analogues bearing a variety of substituents at the 3-position. The methodology involves a palladium-catalyzed addition of hydrazides to 2-chloropyridine, which occurs chemoselectively at the terminal nitrogen atom of the hydrazide, followed by dehydration in acetic acid under microwave irradiation.
Journal of Medicinal Chemistry | 2008
Brad Herberich; Guo-Qiang Cao; Partha P. Chakrabarti; James Richard Falsey; Liping H. Pettus; Robert M. Rzasa; Anthony B. Reed; Andreas Reichelt; Kelvin Sham; Maya C. Thaman; Ryan Wurz; Shimin Xu; Dawei Zhang; Faye Hsieh; Matthew R. Lee; Rashid Syed; Vivian Li; David Grosfeld; Matthew Plant; Bradley Henkle; Lisa Sherman; Scot Middleton; Lu Min Wong; Andrew Tasker
Investigations into the structure-activity relationships (SAR) of a series of phthalazine-based inhibitors of p38 are described. These efforts originated from quinazoline 1 and through rational design led to the development of a series of orally bioavailable, potent, and selective inhibitors. Kinase selectivity was achieved by exploiting a collection of interactions with p38alpha including close contact to Ala157, occupation of the hydrophobic gatekeeper pocket, and a residue flip with Gly110. Substitutions on the phthalazine influenced the pharmacokinetic properties, of which compound 16 displayed the most desirable profile. Oral dosing (0.03 mg/kg) of 16 in rats 1 h prior to LPS challenge gave a >50% decrease in TNFalpha production.
Journal of Medicinal Chemistry | 2012
Marian C. Bryan; Douglas A. Whittington; Elizabeth M. Doherty; James Richard Falsey; Alan C. Cheng; Renee Emkey; Rachael L. Brake; Richard T. Lewis
Piperidine carboxamide 1 was identified as a novel inhibitor of anaplastic lymphoma kinase (ALK enzyme assay IC(50) = 0.174 μM) during high throughput screening, with selectivity over the related kinase insulin-like growth factor-1 (IGF1R). The X-ray cocrystal structure of 1 with the ALK kinase domain revealed an unusual DFG-shifted conformation, allowing access to an extended hydrophobic pocket. Structure-activity relationship (SAR) studies were focused on the rapid parallel optimization of both the right- and left-hand side of the molecule, culminating in molecules with improved potency and selectivity over IGF1R.
Bioorganic & Medicinal Chemistry Letters | 2012
Robert M. Rzasa; Essa Hu; Shannon Rumfelt; Ning Chen; Kristin L. Andrews; Samer Chmait; James Richard Falsey; Wenge Zhong; Adrie D. Jones; Amy Porter; Steven W. Louie; Xiaoning Zhao; James J. S. Treanor; Jennifer R. Allen
We report the discovery of a novel series of biaryl ethers as potent and selective PDE10A inhibitors. Structure-activity studies improved the potency and decreased Pgp-mediated efflux found in the initial compound 4. X-ray crystallographic studies revealed two novel binding modes to the catalytic site of the PDE10A enzyme.
Bioorganic & Medicinal Chemistry Letters | 2013
Marian C. Bryan; James Richard Falsey; Mike Frohn; Andreas Reichelt; Guomin Yao; Michael D. Bartberger; Julie M. Bailis; Leeanne Zalameda; Tisha San Miguel; Elizabeth M. Doherty; John G. Allen
Cdc7 kinase is responsible for the initiation and regulation of DNA replication and has been proposed as a target for cancer therapy. We have identified a class of Cdc7 inhibitors based on a substituted indole core. Synthesis of focused indole and azaindole analogs yielded potent and selective 5-azaindole Cdc7 inhibitors with improved intrinsic metabolic stability (ie 36). In parallel, quantum mechanical conformational analysis helped to rationalize SAR observations, led to a proposal of the preferred binding conformation in the absence of co-crystallography data, and allowed the design of 7-azaindole 37 as a second lead in this series.
ACS Chemical Biology | 2017
Kaustav Biswas; Thomas Nixey; Justin K. Murray; James Richard Falsey; Li Yin; Hantao Liu; Jacinthe Gingras; Brian E. Hall; Brad Herberich; Jerry Ryan Holder; Hongyan Li; Joseph Ligutti; Min-Hwa Jasmine Lin; Dong Liu; Brian Soriano; Marcus Soto; Linh Tran; Christopher M. Tegley; Anrou Zou; Kannan Gunasekaran; Bryan D. Moyer; Liz Doherty; Les P. Miranda
The voltage-gated sodium channel NaV1.7 is a genetically validated pain target under investigation for the development of analgesics. A therapeutic with a less frequent dosing regimen would be of value for treating chronic pain; however functional NaV1.7 targeting antibodies are not known. In this report, we describe NaV1.7 inhibitory peptide-antibody conjugates as an alternate construct for potential prolonged channel blockade through chemical derivatization of engineered antibodies. We previously identified NaV1.7 inhibitory peptide GpTx-1 from tarantula venom and optimized its potency and selectivity. Tethering GpTx-1 peptides to antibodies bifunctionally couples FcRn-based antibody recycling attributes to the NaV1.7 targeting function of the peptide warhead. Herein, we conjugated a GpTx-1 peptide to specific engineered cysteines in a carrier anti-2,4-dinitrophenol monoclonal antibody using polyethylene glycol linkers. The reactivity of 13 potential cysteine conjugation sites in the antibody scaffold was tuned using a model alkylating agent. Subsequent reactions with the peptide identified cysteine locations with the highest conversion to desired conjugates, which blocked NaV1.7 currents in whole cell electrophysiology. Variations in attachment site, linker, and peptide loading established design parameters for potency optimization. Antibody conjugation led to in vivo half-life extension by 130-fold relative to a nonconjugated GpTx-1 peptide and differential biodistribution to nerve fibers in wild-type but not NaV1.7 knockout mice. This study describes the optimization and application of antibody derivatization technology to functionally inhibit NaV1.7 in engineered and neuronal cells.
Archive | 2005
Vinod F. Patel; Joseph L. Kim; Stephanie Geuns-Meyer; Stuart C. Chaffee; Victor J. Cee; Brian L. Hodous; Steven Bellon; Jean-Christophe Harmange; Philip R. Olivieri; Maya C. Thaman; Erin F. DiMauro; John L. Buchanan; David C. Mcgowan; Brian K. Albrecht; Holly L. Deak; Jean E. Bemis; Ryan White; Matthew W. Martin; Gregory J. Habgood; Paul Tempest; Craig E. Masse; William H. Buckner; Bradley J. Herberich; Russell Graceffa; Dawei Zhang; Shimin Xu; Kelvin Sham; Robert M. Rzasa; James Richard Falsey; Partha P. Chakrabarti
Journal of Medicinal Chemistry | 2007
Elizabeth M. Doherty; Christopher Fotsch; Anthony W. Bannon; Yunxin Bo; Ning Chen; Celia Dominguez; James Richard Falsey; Narender R. Gavva; Jodie Katon; Thomas Nixey; Vassil I. Ognyanov; Liping H. Pettus; Robert M. Rzasa; Markian Stec; Sekhar Surapaneni; Rami Tamir; Jiawang Zhu; James J. S. Treanor; Mark H. Norman
Archive | 2007
Dawei Zhang; Andrew Tasker; Kelvin Sham; Partha P. Chakrabarti; James Richard Falsey; Bradley J. Herberich; Liping H. Pettus; Robert M. Rzasa
Archive | 2006
Andrew Tasker; Dawei Zhang; Guo-Qiang Cao; Partha P. Chakrabarti; James Richard Falsey; Bradley J. Herberich; Randall W. Hungate; Liping H. Pettus; Anthony B. Reed; Robert M. Rzasa; Kelvin Sham; Maya C. Thaman; Shimin Xu