Michael J. Forrest

Origin Energy (Australia)

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D. Euan MacIntyre

Center for Advancing Health

Margaret A. Cascieri

Merck & Co., Inc., Rahway, NJ, USA (United States)

Ann E. Weber

Merck & Co., Inc., Rahway, NJ, USA (United States)

Mari R. Candelore

Merck & Co., Inc., Rahway, NJ, USA (United States)

Gary J. Hom

Merck & Co., Inc., Rahway, NJ, USA (United States)

Matthew J. Wyvratt

Merck & Co., Inc., Rahway, NJ, USA (United States)

Michael H. Fisher

Oberlin College

Ester Carballo‐Jane

Quantitative BioSciences

Laurie Tota

Merck & Co., Inc., Rahway, NJ, USA (United States)

Silvi Luell

Merck & Co., Inc., Rahway, NJ, USA (United States)

Cooperative Institutions

Merck & Co., Inc., Rahway, NJ, USA (United States)

266

United States Military Academy

Merck (Japan)

Merck Institute for Science Education

Harvard University

National Institutes of Health

Rutgers, The State University of New Jersey

Princeton University

Bristol-Myers Squibb (United States)

University of Pennsylvania

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Selecting against S1P3 enhances the acute cardiovascular tolerability of 3-(N-benzyl)aminopropylphosphonic acid S1P receptor agonists

Bioorganic & Medicinal Chemistry Letters (2004)

Jeffrey J. Hale George Doherty Leslie M. Toth Sander G. Mills Richard Hajdu

Tolerability

10.1016/j.bmcl.2004.04.070

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Citations (46)

Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity

Bioorganic & Medicinal Chemistry Letters (2005)

Cameron J. Smith Amjad Ali James M. Balkovec Donald W. Graham Milton L. Hammond

Transrepression

Structure–activity relationship

10.1016/j.bmcl.2005.03.027

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Citations (34)

DHI Threshold Effect in Prospect Risking

Proceedings of Offshore Technology Conference (2009)

Rocky Roden Michael J. Forrest Roger Holeywell

10.4043/otc-19983-ms

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Citations (1)

Acute hemodynamic and renal effects of glucagon-like peptide 1 analog and dipeptidyl peptidase-4 inhibitor in rats

Cardiovascular Diabetology (2015)

Xiaoyan Zhou Chin-hu Huang Julie Lao Alessandro Pocai Gail Forrest

Glucagon-like peptide 1 (GLP-1) analogs and dipeptidyl peptidase-4 (DPP4) inhibitors are a newer class of antidiabetics named as incretin-based therapy. In addition to the homeostatic control of glucose, the incretin-based therapy has shown beneficial effects on the cardiovascular system in preclinical and clinical studies. However, there is limited information on their renal effects. To this end, we assessed the acute hemodynamic and renal effects of a GLP-1 analog, Liraglutide, and a DPP4 inhibitor, MK-0626.Experiments were performed in anesthetized male Sprague-Dawley rats. Three ascending doses of Liraglutide (3, 9, and 27 nmol/kg/h) or MK-0626 (1 mg/kg) with or without GLP-1 peptide (2.4, 4.8, or 9.6 pmol/kg/min) were administered. Blood pressure (BP) and heart rate (HR) were recorded from an indwelling catheter. Glomerular filtration rate (GFR) and renal blood flow (RBF) were assessed by inulin and para-aminohippurate clearance, respectively. Renal excretory function was assessed in metabolic studies.Both Liraglutide and MK-0626 plus GLP-1 evoked significant diuretic and natriuretic responses and increased GFR. MK-0626 alone increased RBF. Liraglutide at 27 nmol//kg/h and MK-0626 plus GLP-1 at 9.6 pmol/kg/min also increased HR, whereas BP was not affected.The results of the present study demonstrated that a GLP-1 analog and a DPP4 inhibitor may have beneficial effects on renal sodium and water handling. Additionally, the DPP4 inhibitor, MK-0626, favorably affects renal hemodynamics by increasing RBF. However, exceedingly high levels of GLP-1 receptor agonists may adversely affect the cardiovascular system in acute setting, as demonstrated by an acute increase in HR.

Dipeptidyl peptidase

Incretin

10.1186/s12933-015-0194-3

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Citations (23)

Sphingosine-1-Phosphate Agonists Increase Macrophage Homing, Lymphocyte Contacts, and Endothelial Junctional Complex Formation in Murine Lymph Nodes

The Journal of Immunology (2005)

Irwin Singer Min Tian L. Alexandra Wickham Jeffrey Lin Scaria S. Matheravidathu

The sphingosine-1-phosphate (S1P) receptor agonist, phosphorylated FTY720 (FTY-P), causes lymphopenia, lymphocyte sequestration in mesenteric lymph nodes (MLNs), and immunosuppression. Using multiple techniques to analyze MLN cells harvested from mice treated with S1P receptor agonists, we saw a redistribution of lymphocytes out of nodal sinuses and an expansion of follicles. Although changes in circulating monocytes were not observed with overnight exposure to FTY720, we saw a significant increase in S1P receptor 1 (S1P1)-expressing CD68+ macrophages in subcapsular sinuses of FTY-P-treated MLNs. This was confirmed by quantitative analysis of F4/80+ cells in MLN suspensions. The sinus volume and number of S1P1-positive cells within sinuses were also increased by FTY-P. High endothelial venules and lymphatic endothelium expressed high levels of S1P1, and treatment with FTY-P resulted in intense staining and colocalization of CD31, beta-catenin, and zona occludens 1 in junctions between sinus cells. Transmission electron microscopy showed that FTY-P greatly reduced lymphocyte microvilli and increased cell-cell contacts in the parenchyma. Immunoelectron microscopy revealed that intranodal lymphocytes lacked surface expression of S1P1, whereas S1P1 was evident on the surface and within the cytoplasm of macrophages, endothelial cells, and stromal cells. This subcellular pattern of intranodal receptor distribution was unchanged by treatment with FTY-P. We conclude that S1P1 agonists have profound effects on macrophages and endothelial cells, in addition to inducing lymphopenia.

High endothelial venules

Mesenteric lymph nodes

10.4049/jimmunol.175.11.7151

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Citations (90)

Modification of leukocyte adhesion in spontaneously hypertensive rats by adrenal corticosteroids

Journal of Leukocyte Biology (1995)

Hidekazu Suzuki Benjamin W. Zweifach Michael J. Forrest Geert W. Schmid‐Schönbein

Leukocyte adhesion is a key factor in the pathogenesis of organ injury following a variety of stimuli. In this study we have addressed the role of leukocyte adhesion in hypertensives as a risk factor for organ injury. In the spontaneously hypertensive rat (SHR), the number of circulating leukocytes and their level of activation are significantly increased compared with its normotensive control, the Wistar-Kyoto rat (WKY). We have demonstrated that elevated levels of glucocorticoid in SHR suppress P-selectin-mediated leukocyte-endothelial interaction in the microcirculation. It is possible that the disturbance in leukocyte-endothelial interactions may result in an elevated number of leukocytes in the circulation. The aim of the present study was to investigate the contribution of the adrenal glands to the disturbance in leukocyte behavior in SHR by subjecting the animals to bilateral adrenalectomy and investigating the effect of hydrocortisone. In addition, we have studied by immunohistochemistry the expression of the endothelial adhesion molecule, P-selectin, in response to histamine in the mesenteric venules of normal and adrenalectomized SHR and WKY. The elevated blood pressure, above-normal leukocyte counts, and elevated number of activated neutrophils (nitroblue tetrazolium test) in SHR were blunted after adrenalectomy. The blunted histamine-induced leukocyte-endothelial interaction in the mesenteric venules of SHR was restored after adrenalectomy. Treatment with hydrocortisone significantly attenuated the elevated leukocyte adhesion in the adrenalectomized SHR as well as in WKY. The suppressed P-selectin expression in SHR mesentery was restored after adrenalectomy. In conclusion, the subnormal leukocyte-endothelial interaction in response to an inflammatory stimulation in SHR is abolished after adrenalectomy, suggesting a relationship between the altered leukocyte adhesiveness and the adrenal corticosteroids in hypertensives.

10.1002/jlb.57.1.20

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Citations (57)

Discovery of Potent 3,5-Diphenyl-1,2,4-oxadiazole Sphingosine-1-phosphate-1 (S1P₁) Receptor Agonists with Exceptional Selectivity against S1P₂ and S1P₃

Journal of Medicinal Chemistry (2005)

Zhen Li Weirong Chen Jeffrey J. Hale Christopher L. Lynch Sander G. Mills

A class of 3,5-diphenyl-1,2,4-oxadiazole based compounds have been identified as potent sphingosine-1-phosphate-1 (S1P1) receptor agonists with minimal affinity for the S1P2 and S1P3 receptor subtypes. Analogue 26 (S1P1 IC50 = 0.6 nM) has an excellent pharmacokinetics profile in the rat and dog and is efficacious in a rat skin transplant model, indicating that S1P3 receptor agonism is not a component of immunosuppressive efficacy.

Sphingosine-1-phosphate receptor

Oxadiazole

Sphingosine Kinase

IC50

10.1021/jm0503244

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Citations (99)

Platelet transfusion reverses bleeding evoked by triple anti-platelet therapy including vorapaxar, a novel platelet thrombin receptor antagonist

European Journal of Pharmacology (2015)

Tian‐Quan Cai L. Alexandra Wickham Gary R. Sitko Maria Strainer Michener Richard F. Raubertas

Bleeding time

Platelet Transfusion