Search results for: Andrew D. Howard

Items from 1 to 20 out of 42 results

article

Corrigendum to “Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects” [Bioorg. Med. Chem. Lett. 26 (2016) 5724–5728]

Matthew Lombardo, Kate Bender, Clare London, Michael A. Plotkin, more

Bioorganic & Medicinal Chemistry Letters > 2017 > 27 > 5 > 1333

article

Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects

Matthew Lombardo, Kate Bender, Clare London, Michael A. Plotkin, more

Bioorganic & Medicinal Chemistry Letters > 2016 > 26 > 23 > 5724-5728

The transformation of an aryloxybutanoic acid ultra high-throughput screening (uHTS) hit into a potent and selective series of G-protein coupled receptor 120 (GPR120) agonists is reported. uHTS hit 1 demonstrated an excellent rodent pharmacokinetic profile and selectivity over the related fatty acid receptor GPR40, but only modest GPR120 potency. Optimization of the “left-hand” aryl group led to compound...

article

The ESRD Quality Incentive Program: The Current Limitations of Evidence and Data to Develop Measures, Drive Improvement, and Incentivize Outcomes

Louis H. Diamond, Andrew D. Howard

Advances in Chronic Kidney Disease > 2016 > 23 > 6 > 377-384

This article describes the current state of facilitating the integration of evidence into practice to support initiatives focused on patients with ESRD. We will use the Centers for Medicare and Medicaid Services (CMS) ESRD Quality Incentive Program (QIP) as an example, including a description of the health information infrastructure needed to support the translation of evidence into practice and some...

article

Duodenal‐jejunal bypass surgery induces hepatic lipidomic alterations associated with ameliorated hepatic steatosis in mice

Jin Shang, Jose M. Castro‐Perez, Xiaolan Shen, Yonghua Zhu, more

Obesity > 24 > 9 > 1938 - 1945

Objective Bariatric surgery induces weight loss and improvement of insulin resistance; one aspect of both is an amelioration of hepatic steatosis. This study was undertaken to assess the changes in the hepatic lipidome after duodenal‐jejunal bypass (DJB) surgery. Methods A DJB surgical model was developed and characterized in diet‐induced obese mice. In comparison with sham‐operated mice, an unbiased...

article

SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

Shuwen He, Peter H. Dobbelaar, Liangqin Guo, Zhixiong Ye, more

Bioorganic & Medicinal Chemistry Letters > 2016 > 26 > 6 > 1529-1535

MK-4256, a tetrahydro-β-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-β-carboline...

article

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Zhong Lai, Shuwen He, Edward C. Sherer, Zhicai Wu, more

Bioorganic & Medicinal Chemistry Letters > 2015 > 25 > 17 > 3520-3525

We report SAR studies on a novel non-peptidic somatostatin receptor 3 (SSTR3) agonist lead series derived from (4-phenyl-1H-imidazol-2-yl)methanamine. This effort led to the discovery of a highly potent low molecular weight SSTR3 agonist 5c (EC₅₀=5.2nM, MW=359). The results from molecular overlays of 5c onto the L-129 structure indicate good alignment, and two main differences of the proposed overlays...

article

Correlates of change in health care worker seasonal influenza vaccination rates among dialysis facilities

Janet R. Lynch, Nancy Armistead, Brandy B. Vinson, Andrew D. Howard

AJIC: American Journal of Infection Control > 2015 > 43 > 4 > 409-411

We conducted a campaign to increase seasonal influenza vaccination of dialysis health care workers (HCWs) in the District of Columbia, Maryland, Virginia, and West Virginia. Between the 2010-2011 and 2011-2012 influenza seasons we examined the correlates of change. HCW vaccination rates improved significantly (P < .01) from a mean ± standard deviation of 64.5 ± 27.4 to 72.7 ± 23.1. Evidence-based...

article

GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo

Maria Hauge, Marie A. Vestmar, Anna S. Husted, Jeppe P. Ekberg, more

Molecular Metabolism > 2015 > 4 > 1 > 3-14

GPR40 (FFAR1), a clinically proven anti-diabetes target, is a Gq-coupled receptor for long chain fatty acids (LCFA) stimulating insulin secretion directly and mediating a major part of the dietary triglyceride-induced secretion of the incretins GLP-1 and GIP. In phase-II studies the GPR40 agonist TAK-875 decreased blood glucose but surprisingly without stimulating incretins.Here we find that GPR40...

article

Fistula First Breakthrough Initiative (FFBI): Lessons About Arteriovenous Fistula Prevalence Goals

Andrew D. Howard, Robin S. Howard, Stuart L. Goldstein, Klemens B. Meyer

American Journal of Kidney Diseases > 2013 > 61 > 3 > 523-525

article

3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists

Shawn P. Walsh, Alexandra Severino, Changyou Zhou, Jiafang He, more

Bioorganic & Medicinal Chemistry Letters > 2011 > 21 > 11 > 3390-3394

The design, synthesis, and structure–activity relationship (SAR) for a series of β-substituted 3-(4-aryloxyaryl)propanoic acid GPR40 agonists is described. Systematic replacement of the pendant aryloxy group led to identification of potent GPR40 agonists. In order to identify candidates suitable for in vivo validation of the target, serum shifted potency and pharmacokinetic properties were determined...

article

Design of potent and selective GPR119 agonists for type II diabetes

Jason W. Szewczyk, John Acton, Alan D. Adams, Gary Chicchi, more

Bioorganic & Medicinal Chemistry Letters > 2011 > 21 > 9 > 2665-2669

Screening of the Merck sample collection identified compound 1 as a weakly potent GPR119 agonist (hEC ₅₀ =3600nM). Dual termini optimization of 1 led to compound 36 having improved potency, selectivity, and formulation profile, however, modest physical properties (PP) hindered its utility. Design of a new core containing a cyclopropyl restriction yielded further PP improvements and when combined...

article

Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity

Jian Liu, Shuwen He, Tianying Jian, Peter H. Dobbelaar, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 7 > 2074-2077

This Letter describes a series of potent and selective BRS-3 agonists containing a biarylethylimidazole pharmacophore. Extensive SAR studies were carried out with different aryl substitutions. This work led to the identification of a compound 2-{2-[4-(pyridin-2-yl)phenyl]ethyl}-5-(2,2-dimethylbutyl)-1H-imidazole 9 with excellent binding affinity (IC ₅₀ =18nM, hBRS-3) and functional agonist...

article

Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists

Shuwen He, Peter H. Dobbelaar, Jian Liu, Tianying Jian, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 6 > 1913-1917

We report SAR studies on a novel non-peptidic bombesin receptor subtype-3 (BRS-3) agonist lead series derived from high-throughput screening hit RY-337. This effort led to the discovery of compound 22e with significantly improved potency at both rodent and human BRS-3.

article

Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity

Xiao-Ming Guan, Howard Chen, Peter H. Dobbelaar, Yan Dong, more

Cell Metabolism > 2010 > 11 > 2 > 101-112

Bombesin receptor subtype 3 (BRS-3) is a G protein coupled receptor whose natural ligand is unknown. We developed potent, selective agonist (Bag-1, Bag-2) and antagonist (Bantag-1) ligands to explore BRS-3 function. BRS-3-binding sites were identified in the hypothalamus, caudal brainstem, and several midbrain nuclei that harbor monoaminergic cell bodies. Antagonist administration increased food intake...

article

Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists

Changyou Zhou, Cheng Tang, Eric Chang, Min Ge, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 3 > 1298-1301

Systematic structure–activity relationship (SAR) studies of a screening lead led to the discovery of a series of thiazolidinediones (TZDs) as potent GPR40 agonists. Among them, compound C demonstrated an acute mechanism-based glucose-lowering in an intraperitoneal glucose tolerance test (IPGTT) in lean mice, while no effects were observed in GPR40 knock-out mice.

article

Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes

James Mu, Aleksandr Petrov, George J. Eiermann, John Woods, more

European Journal of Pharmacology > 2009 > 623 > 1-3 > 148-154

Inhibition of dipeptidyl peptidase-4 (DPP-4) activity has been shown to improve glycemic control in patients with type 2 diabetes by prolonging and potentiating the actions of incretin hormones. This study is designed to determine the effects of the DPP-4 inhibitor sitagliptin on improving islet function in a mouse model of insulin resistance and insulin secretion defects. ICR mice were pre-treated...

article

Discovery and optimization of novel 4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl)phenyl]benzenesulfonamide ghrelin receptor antagonists

Alexander Pasternak, Stephen D. Goble, Reynalda K. deJesus, Donna L. Hreniuk, more

Bioorganic & Medicinal Chemistry Letters > 2009 > 19 > 21 > 6237-6240

This Letter describes optimization of ghrelin receptor antagonists and inverse agonists starting from a screening hit.

article

Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice

Enpeng Zhao, Mark P. Keller, Mary E. Rabaglia, Angie T. Oler, more

Mammalian Genome > 2009 > 20 > 8 > 476-485

Type 2 diabetes results from severe insulin resistance coupled with a failure of β cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19–22-nucleotide RNA molecules that potentially regulate the expression of thousands...

article

4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists

Jinlong Jiang, Peter Lin, Myle Hoang, Lehua Chang, more

Bioorganic & Medicinal Chemistry Letters > 2006 > 16 > 20 > 5275-5279

Structure–activity relationships of a 4-aminoquinoline MCH1R antagonist lead series were explored by synthesis of analogs with modifications at the 2-, 4-, and 6-positions of the original HTS hit. Improvements to the original screening lead included lipophilic groups at the 2-position and biphenyl, cyclohexyl phenyl, and hydrocinnamyl carboxamides at the 6-position. Modifications of the 4-amino group...

article

Long-Term Posttransplantation Care: The Expanding Role of Community Nephrologists

Andrew D. Howard

American Journal of Kidney Diseases > 2006 > 47 > 4 Supplement 2 > S111-S124

Improvements in transplantation practices, immunosuppressive agents, and management of comorbid conditions have led to better outcomes for kidney transplant recipients. Transplantation has become the treatment of choice for patients with end-stage renal disease (ESRD). This has resulted in continued growth in the number of patients living with a functioning kidney allograft as a percentage of the...

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Search results for: Andrew D. Howard

Corrigendum to “Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects” [Bioorg. Med. Chem. Lett. 26 (2016) 5724–5728]

Discovery of benzofuran propanoic acid GPR120 agonists: From uHTS hit to mechanism-based pharmacodynamic effects

The ESRD Quality Incentive Program: The Current Limitations of Evidence and Data to Develop Measures, Drive Improvement, and Incentivize Outcomes

Duodenal‐jejunal bypass surgery induces hepatic lipidomic alterations associated with ameliorated hepatic steatosis in mice

SAR exploration at the C-3 position of tetrahydro-β-carboline sstr3 antagonists

Discovery of substituted (4-phenyl-1H-imidazol-2-yl)methanamine as potent somatostatin receptor 3 agonists

Correlates of change in health care worker seasonal influenza vaccination rates among dialysis facilities

GPR40 (FFAR1) – Combined Gs and Gq signaling in vitro is associated with robust incretin secretagogue action ex vivo and in vivo

Fistula First Breakthrough Initiative (FFBI): Lessons About Arteriovenous Fistula Prevalence Goals

3-Substituted 3-(4-aryloxyaryl)-propanoic acids as GPR40 agonists

Design of potent and selective GPR119 agonists for type II diabetes

Synthesis and SAR of derivatives based on 2-biarylethylimidazole as bombesin receptor subtype-3 (BRS-3) agonists for the treatment of obesity

Discovery of substituted biphenyl imidazoles as potent, bioavailable bombesin receptor subtype-3 agonists

Regulation of Energy Homeostasis by Bombesin Receptor Subtype-3: Selective Receptor Agonists for the Treatment of Obesity

Discovery of 5-aryloxy-2,4-thiazolidinediones as potent GPR40 agonists

Inhibition of DPP-4 with sitagliptin improves glycemic control and restores islet cell mass and function in a rodent model of type 2 diabetes

Discovery and optimization of novel 4-[(aminocarbonyl)amino]-N-[4-(2-aminoethyl)phenyl]benzenesulfonamide ghrelin receptor antagonists

Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice

4-Aminoquinoline melanin-concentrating hormone 1-receptor (MCH1R) antagonists

Long-Term Posttransplantation Care: The Expanding Role of Community Nephrologists

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