Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Nicole Cathleen Goodwin is active.

Publication


Featured researches published by Nicole Cathleen Goodwin.


Clinical Pharmacology & Therapeutics | 2012

LX4211, a Dual SGLT1/SGLT2 Inhibitor, Improved Glycemic Control in Patients With Type 2 Diabetes in a Randomized, Placebo‐Controlled Trial

Brian Zambrowicz; Joel Freiman; P M Brown; Kenny Frazier; Anne Turnage; J Bronner; D Ruff; Phillip Banks; Faika Mseeh; D B Rawlins; Nicole Cathleen Goodwin; R Mabon; Bryce Alden Harrison; Alan Wilson; Arthur T. Sands; David R. Powell

Thirty‐six patients with type 2 diabetes mellitus (T2DM) were randomized 1:1:1 to receive a once‐daily oral dose of placebo or 150 or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 for 28 days. Relative to placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2‐mediated renal glucose reabsorption; markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA1c; and significantly lowered serum triglycerides. LX4211 also mediated trends for lower weight, lower blood pressure, and higher glucagon‐like peptide‐1 levels. In a follow‐up single‐dose study in 12 patients with T2DM, LX4211 (300 mg) significantly increased glucagon‐like peptide‐1 and peptide YY levels relative to pretreatment values, probably by delaying SGLT1‐mediated intestinal glucose absorption. In both studies, LX4211 was well tolerated without evidence of increased gastrointestinal side effects. These data support further study of LX4211‐mediated dual SGLT1/SGLT2 inhibition as a novel mechanism of action in the treatment of T2DM.


Journal of Medicinal Chemistry | 2009

Novel l-Xylose Derivatives as Selective Sodium-Dependent Glucose Cotransporter 2 (SGLT2) Inhibitors for the Treatment of Type 2 Diabetes

Nicole Cathleen Goodwin; Ross Mabon; Bryce Alden Harrison; Zheng Y. Almstead; Yiling Xie; Jason P. Healy; Lindsey Buhring; Christopher M. DaCosta; Jennifer Bardenhagen; Faika Mseeh; Qingyun Liu; Amr Nouraldeen; Alan Wilson; S. David Kimball; David R. Powell; David B. Rawlins

The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo.


ACS Medicinal Chemistry Letters | 2015

Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma.

Bryce Alden Harrison; Zheng Y. Almstead; Hugh Alfred Burgoon; Michael Gardyan; Nicole Cathleen Goodwin; Jason P. Healy; Ying Liu; Ross Mabon; Brett Marinelli; Lakshman Samala; Yulian Zhang; Terry R. Stouch; N. Andrew Whitlock; Suma Gopinathan; Beth McKnight; Shuli Wang; Nita Patel; Alan Wilson; Brian D. Hamman; Dennis S. Rice; David B. Rawlins

The structure of LX7101, a dual LIM-kinase and ROCK inhibitor for the treatment of ocular hypertension and associated glaucoma, is disclosed. Previously reported LIM kinase inhibitors suffered from poor aqueous stability due to solvolysis of the central urea. Replacement of the urea with a hindered amide resulted in aqueous stable compounds, and addition of solubilizing groups resulted in a set of compounds with good properties for topical dosing in the eye and good efficacy in a mouse model of ocular hypertension. LX7101 was selected as a clinical candidate from this group based on superior efficacy in lowering intraocular pressure and a good safety profile. LX7101 completed IND enabling studies and was tested in a Phase 1 clinical trial in glaucoma patients, where it showed efficacy in lowering intraocular pressure.


ACS Medicinal Chemistry Letters | 2015

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.

Nicole Cathleen Goodwin; Giovanni Cianchetta; Hugh Alfred Burgoon; Jason P. Healy; Ross Mabon; Eric Strobel; Jason Allen; Shuli Wang; Brian D. Hamman; David B. Rawlins

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.


Journal of Medicinal Chemistry | 2017

Discovery of LX2761, a Sodium-Dependent Glucose Cotransporter 1 (SGLT1) Inhibitor Restricted to the Intestinal Lumen, for the Treatment of Diabetes

Nicole Cathleen Goodwin; Zhi-Ming Ding; Bryce Alden Harrison; Eric Strobel; Angela L. Harris; Melinda Smith; Andrea Y. Thompson; Wendy Xiong; Faika Mseeh; Debra Bruce; Damaris S. Diaz; Suma Gopinathan; Ling Li; Emily O’Neill; Mary Thiel; Alan Wilson; Kenneth G. Carson; David R. Powell; David B. Rawlins

The increasing number of people afflicted with diabetes throughout the world is a major health issue. Inhibitors of the sodium-dependent glucose cotransporters (SGLT) have appeared as viable therapeutics to control blood glucose levels in diabetic patents. Herein we report the discovery of LX2761, a locally acting SGLT1 inhibitor that is highly potent in vitro and delays intestinal glucose absorption in vivo to improve glycemic control.


Journal of Pharmacology and Experimental Therapeutics | 2017

LX2761, a Sodium/Glucose Cotransporter 1 Inhibitor Restricted to the Intestine, Improves Glycemic Control in Mice

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

LP-925219 maximizes urinary glucose excretion in mice by inhibiting both renal SGLT1 and SGLT2

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.


Archive | 2007

Phlorizin analogs as inhibitors of sodium glucose co-transporter 2

Nicole Cathleen Goodwin; Bryce Alden Harrison; S. David Kimball; Ross Mabon; David B. Rawlins


Archive | 2008

Methods and compounds useful for the preparation of sodium glucose co-transporter 2 inhibitors

Nicole Cathleen Goodwin; Bryce Alden Harrison; Shinya Iimura; Ross Mabon; Qiuling Song; Wenxue Wu; Jie Yan; Haiming Zhang; Matthew Mangzhu Zhao


Archive | 2009

LIMK2 inhibitors, compositions comprising them and methods of their use

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

Collaboration


Dive into the Nicole Cathleen Goodwin's collaboration.

Top Co-Authors

Avatar
Top Co-Authors

Avatar

Ross Mabon

Lexicon Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Alan Wilson

Lexicon Pharmaceuticals

View shared research outputs
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge