James G. Robertson

Wei Meng; Bruce A. Ellsworth; Alexandra A. Nirschl; Peggy J. McCann; Manorama Patel; Ravindar N Girotra; Gang Wu; Philip M. Sher; Eamonn P. Morrison; Scott A. Biller; Robert Zahler; Prashant P. Deshpande; Annie Pullockaran; Deborah Hagan; Nathan Morgan; Joseph R. Taylor; Mary T. Obermeier; William G. Humphreys; Ashish Khanna; Lorell Discenza; James G. Robertson; Aiying Wang; Songping Han; John R. Wetterau; Evan B. Janovitz; Oliver P. Flint; Jean M. Whaley; William N. Washburn

The C-aryl glucoside 6 (dapagliflozin) was identified as a potent and selective hSGLT2 inhibitor which reduced blood glucose levels in a dose-dependent manner by as much as 55% in hyperglycemic streptozotocin (STZ) rats. These findings, combined with a favorable ADME profile, have prompted clinical evaluation of dapagliflozin for the treatment of type 2 diabetes.

Charles J. Andres; Joanne J. Bronson; Stanley D'andrea; Milind Deshpande; Paul Falk; Katharine A. Grant-Young; William E. Harte; Hsu Tso Ho; Peter F. Misco; James G. Robertson; David Stock; Yaxiong Sun; Ann W. Walsh

4-Thiazolidinones were synthesized and evaluated for their ability to inhibit the bacterial enzyme MurB. Selected 4-thiazolidinones displayed activity against the enzyme in vitro. This activity, coupled with the design principles of the thiazolidinones, supports the postulate that 4-thiazolidinones may be recognized as diphosphate mimics by a biological selector.

Guohua Zhao; Chet Kwon; Aiying Wang; James G. Robertson; Jovita Marcinkeviciene; Rex A. Parker; Mark S. Kirby; Lawrence G. Hamann

Synthesis and structure-activity relationship of a series of substituted piperidinyl glycine 2-cyano-4,5-methano pyrroline DPP-IV inhibitors are described. Improvement of the inhibitory activity and chemical stability of this series of compounds was respectively achieved by the introduction of bulky groups at the 4-position and 1-position of the piperidinyl glycine, leading to a series of potent and stable DPP-IV inhibitors.

Aiying Wang; Yanting Huang; Prakash Taunk; David R. Magnin; Krishnendu Ghosh; James G. Robertson

Using available commercial robotics and instrumentation, we developed a fully automated and rigorous steady state enzyme kinetic assay for dipeptidyl peptidase IV (DPP IV; E.C. 3.4.14.5). The automated assay was validated with isoleucyl thiazolidide, a potent inhibitor of DPP IV with K(is)=110nM. Signal window analysis indicated that the assay had a 98% probability of detecting an inhibitor yielding 15% inhibition, with a predicted false positive rate of 0.13%. A mechanistic inhibition version of the automated assay was validated with isoleucyl 4-cyanothiazolidide, a very potent inhibitor of DPP IV. Isoleucyl 4-cyanothiazolidide was a competitive inhibitor of purified porcine DPP IV with K(is)=1 nM. Similar K(is) values were obtained for purified rat DPP IV and for DPP IV activity in human plasma from normal and diabetic donors. The pH dependence of K(is) for isoleucyl 4-cyanothiazolidide yielded a bell-shaped profile, with pK(a)=5.0 and pK(b)=7.6. To date, over 100,000 data points have been generated in profiling targeted compound libraries and in the analysis of tight-binding inhibitors of DPP IV. The data also show that robotic analysis is capable of producing full mechanistic inhibition analysis in a timely fashion to support drug discovery.

David J. Augeri; Jeffrey A. Robl; David A. Betebenner; David R. Magnin; Ashish Khanna; James G. Robertson; Aiying Wang; Ligaya M. Simpkins; Prakash Taunk; Qi Huang; Songping Han; Benoni E. Abboa-Offei; Michael Cap; Li Xin; Li Tao; Effie Tozzo; Gustav Welzel; Donald M. Egan; Jovita Marcinkeviciene; Shu Y. Chang; Scott A. Biller; Mark S. Kirby; Rex A. Parker; Lawrence G. Hamann

Bennett T. Farmer; Keith L. Constantine; Valentina Goldfarb; Mark S. Friedrichs; Michael Wittekind; Joseph Yanchunas; James G. Robertson; Luciano Mueller

James G. Robertson

David R. Magnin; Jeffrey A. Robl; Richard B. Sulsky; David J. Augeri; Yanting Huang; Ligaya M. Simpkins; Prakash Taunk; David A. Betebenner; James G. Robertson; Benoni E. Abboa-Offei; Aiying Wang; Michael Cap; Li Xin; Li Tao; Doree Sitkoff; Mary F. Malley; Jack Z. Gougoutas; Ashish Khanna; Qi Huang; Songping Han; Rex A. Parker; Lawrence G. Hamann

Bruce A. Ellsworth; Wei Meng; Manorama Patel; Ravindar N Girotra; Gang Wu; Philip M. Sher; Deborah Hagan; Mary T. Obermeier; William G. Humphreys; James G. Robertson; Aiying Wang; Songping Han; Thomas L. Waldron; Nathan Morgan; Jean M. Whaley; William N. Washburn

Keith L. Constantine; Luciano Mueller; Valentina Goldfarb; Michael Wittekind; William J. Metzler; Joseph Yanchunas; James G. Robertson; Mary F. Malley; Mark S. Friedrichs; Bennett T. Farmer