David Brent Rawlins
Lexicon Pharmaceuticals
Network
Latest external collaboration on country level. Dive into details by clicking on the dots.
Publication
Featured researches published by David Brent Rawlins.
Journal of Pharmacology and Experimental Therapeutics | 2017
David R. Powell; Melinda Smith; Deon Doree; Angela L. Harris; Jennifer Greer; Christopher M. DaCosta; Andrea Y. Thompson; Sabrina Jeter-Jones; Wendy Xiong; Kenneth G. Carson; Nicole Cathleen Goodwin; Bryce Alden Harrison; David Brent Rawlins; Eric Strobel; Suma Gopinathan; Alan Wilson; Faika Mseeh; Brian Zambrowicz; Zhi-Ming Ding
LX2761 is a potent sodium/glucose cotransporter 1 inhibitor restricted to the intestinal lumen after oral administration. Studies presented here evaluated the effect of orally administered LX2761 on glycemic control in preclinical models. In healthy mice and rats treated with LX2761, blood glucose excursions were lower and plasma total glucagon-like peptide-1 (GLP-1) levels higher after an oral glucose challenge; these decreased glucose excursions persisted even when the glucose challenge occurred 15 hours after LX2761 dosing in ad lib-fed mice. Further, treating mice with LX2761 and the dipeptidyl-peptidase 4 inhibitor sitagliptin synergistically increased active GLP-1 levels, suggesting increased LX2761-mediated release of GLP-1 into the portal circulation. LX2761 also lowered postprandial glucose, fasting glucose, and hemoglobin A1C, and increased plasma total GLP-1, during long-term treatment of mice with either early- or late-onset streptozotocin-diabetes; in the late-onset cohort, LX2761 treatment improved survival. Mice and rats treated with LX2761 occasionally had diarrhea; this dose-dependent side effect decreased in severity and frequency over time, and LX2761 doses were identified that decreased postprandial glucose excursions without causing diarrhea. Further, the frequency of LX2761-associated diarrhea was greatly decreased in mice either by gradual dose escalation or by pretreatment with resistant starch 4, which is slowly digested to glucose in the colon, a process that primes the colon for glucose metabolism by selecting for glucose-fermenting bacterial species. These data suggest that clinical trials are warranted to determine if LX2761 doses and dosing strategies exist that provide improved glycemic control combined with adequate gastrointestinal tolerability in people living with diabetes.
Pharmacology Research & Perspectives | 2015
David R. Powell; Melinda Smith; Deon Doree; Angela L. Harris; Wendy Xiong; Faika Mseeh; Alan Wilson; Suma Gopinathan; Damaris Diaz; Nicole Cathleen Goodwin; Bryce Alden Harrison; Eric Strobel; David Brent Rawlins; Kenneth G. Carson; Brian Zambrowicz; Zhi-Ming Ding
Sodium‐glucose cotransporter 2 (SGLT2) inhibitors are a new class of oral anti‐diabetic agents that improve glycemic control by inhibiting SGLT2‐mediated renal glucose reabsorption. Currently available agents increase urinary glucose excretion (UGE) to <50% of maximal values because they do not inhibit SGLT1, which reabsorbs >50% of filtered glucose when SGLT2 is completely inhibited. This led us to test whether LP‐925219, a small molecule dual SGLT1/SGLT2 inhibitor, increases UGE to maximal values in wild‐type (WT) mice. We first tested LP‐925219 inhibition of glucose transport by HEK293 cells expressing SGLT1 or SGLT2, and then characterized LP‐925219 pharmacokinetics. We found that LP‐925219 was a potent inhibitor of mouse SGLT1 (IC50 = 22.6 nmol/L) and SGLT2 (IC50 = 0.5 nmol/L), and that a 10 mg/kg oral dose was bioavailable (87%) with a long half‐life (7 h). We next delivered LP‐925219 by oral gavage to WT, SGLT1 knockout (KO), SGLT2 KO, and SGLT1/SGLT2 double KO (DKO) mice and measured their 24‐h UGE. We found that, in vehicle‐treated mice, DKO UGE was maximal and SGLT2 KO, SGLT1 KO, and WT UGEs were 30%, 2%, and 0.2% of maximal, respectively; we also found that LP‐925219 dosed at 60 mg/kg twice daily increased UGE of SGLT1 KO, SGLT2 KO, and WT mice to DKO UGE levels. These findings show that orally available dual SGLT1/SGLT2 inhibitors can maximize 24‐h UGE in mammals, and suggest that such agents merit further evaluation for their potential, in diabetic patients, to achieve better glycemic control than is achieved using selective SGLT2 inhibitors.
Journal of Chromatography B | 2014
Leonard O. Hargiss; Greg Zipp; Theodore C. Jessop; Xuejun Sun; Philip E. Keyes; David Brent Rawlins; Zhi Liang; Kum Joo Park; Huizhong Gu
An ultra high-pressure liquid chromatography/mass spectrometry (UHPLC/MS) separation and analysis method has been devised for open access analysis of synthetic reactions used in the production of DNA-encoded chemical libraries. The aqueous mobile phase is 100mM hexafluoroisopropanol and 8.6mM triethylamine; the organic mobile phase is methanol. The UHPLC separation uses a C18 OST column (50mm×2.1mm×1.7μm) at 60°C, with a flow rate of 0.6mL/min. Gradient concentration is from 10 to 40% B in 1.0min, increasing to 95% B at 1.2min. Cycle time was about 5min. This method provides a detection limit of a 20-mer oligonucleotide by mass spectrometry of better than 1pmol on-column. Linear UV response for 20-mer extends from 2 to 200pmol/μL in concentration, same-day relative average deviations are less than 5% and bias (observed minus expected) is less than 10%. Deconvoluted mass spectra are generated for components in the predicted mass range using a maximum entropy algorithm. Mass accuracy of deconvoluted spectra is typically 20ppm or better for isotopomers of oligonucleotides up to 7000Da.
Archive | 2006
David Brent Rawlins; Michael Victor Voronkov; Yulian Zhang
Archive | 2009
Hugh Alfred Burgoon; Nicole Cathleen Goodwin; Bryce Alden Harrison; Jason P. Healy; Ying Liu; Ross Mabon; Brett Marinelli; David Brent Rawlins; Dennis S. Rice; Norris Andrew Whitlock
Archive | 2007
Nicole Cathleen Goodwin; Bryce Alden Harrison; Spencer David Kimball; Ross Mabon; David Brent Rawlins
Archive | 2008
Bryce Alden Harrison; Spencer David Kimball; Ross Mabon; David Brent Rawlins
Archive | 2013
Kenneth G. Carson; Nicole Cathleen Goodwin; Bryce Alden Harrison; David Brent Rawlins; Eric Strobel; Brian Zambrowicz
Archive | 2010
Bryce Alden Harrison; Spencer David Kimball; Ross Mabon; David Brent Rawlins
Archive | 2011
Nicole Cathleen Goodwin; David Brent Rawlins