Publications by authors named "Bradford Hamilton"

12 Publications

  • Page 1 of 1

The RESOLUTE consortium: unlocking SLC transporters for drug discovery.

Authors:
Giulio Superti-Furga Daniel Lackner Tabea Wiedmer Alvaro Ingles-Prieto Barbara Barbosa Enrico Girardi Ulrich Goldmann Bettina Gürtl Kristaps Klavins Christoph Klimek Sabrina Lindinger Eva Liñeiro-Retes André C Müller Svenja Onstein Gregor Redinger Daniela Reil Vitaly Sedlyarov Gernot Wolf Matthew Crawford Robert Everley David Hepworth Shenping Liu Stephen Noell Mary Piotrowski Robert Stanton Hui Zhang Salvatore Corallino Andrea Faedo Maria Insidioso Giovanna Maresca Loredana Redaelli Francesca Sassone Lia Scarabottolo Michela Stucchi Paola Tarroni Sara Tremolada Helena Batoulis Andreas Becker Eckhard Bender Yung-Ning Chang Alexander Ehrmann Anke Müller-Fahrnow Vera Pütter Diana Zindel Bradford Hamilton Martin Lenter Diana Santacruz Coralie Viollet Charles Whitehurst Kai Johnsson Philipp Leippe Birgit Baumgarten Lena Chang Yvonne Ibig Martin Pfeifer Jürgen Reinhardt Julian Schönbett Paul Selzer Klaus Seuwen Charles Bettembourg Bruno Biton Jörg Czech Hélène de Foucauld Michel Didier Thomas Licher Vincent Mikol Antje Pommereau Frédéric Puech Veeranagouda Yaligara Aled Edwards Brandon J Bongers Laura H Heitman Ad P IJzerman Huub J Sijben Gerard J P van Westen Justine Grixti Douglas B Kell Farah Mughal Neil Swainston Marina Wright-Muelas Tina Bohstedt Nicola Burgess-Brown Liz Carpenter Katharina Dürr Jesper Hansen Andreea Scacioc Giulia Banci Claire Colas Daniela Digles Gerhard Ecker Barbara Füzi Viktoria Gamsjäger Melanie Grandits Riccardo Martini Florentina Troger Patrick Altermatt Cédric Doucerain Franz Dürrenberger Vania Manolova Anna-Lena Steck Hanna Sundström Maria Wilhelm Claire M Steppan

Nat Rev Drug Discov 2020 07;19(7):429-430

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http://dx.doi.org/10.1038/d41573-020-00056-6DOI Listing
July 2020

SGLT6 - A pharmacological target for the treatment of obesity?

Adipocyte 2018 11;7(4):277-284. Epub 2018 Oct 11.

a CardioMetabolic Diseases Research , Boehringer-Ingelheim Pharma GmbH & Co. KG , Biberach an der Riss , Germany.

Despite increased knowledge of nutrient intake regulation and energy homeostasis, treatment options for obesity remain limited. Food reward consists of two branches: gustatory and post-ingestive nutritive information. Drosophila lacking dSLC5A11 (sodium/glucose cotransporter 6-SGLT6) prefer L-glucose over D-glucose independently of their state of satiety. Human SGLT6 is an active transporter of myo-inositol and D-glucose. We investigated expression of SGLT6 in human tissue and found a significant expression in the small intestine and brain. The preference between a metabolizable and a non-metabolizable sugar was tested in 3 mouse models with a selective and potent SGLT6 inhibitor. No influence on sugar preference was seen with SGLT6 inhibition. These studies suggest that SGLT6 does not play a significant role in nutrient sensing in mammals.
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http://dx.doi.org/10.1080/21623945.2018.1516098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768193PMC
September 2019

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11β hydroxysteroid dehydrogenase type 1 inhibitor.

Bioorg Med Chem 2017 07 29;25(14):3649-3657. Epub 2017 Apr 29.

Medicinal Chemistry, Vitae Pharmaceuticals, Inc, 502 West Office Center Drive, Fort Washington, PA 19034, United States.

A potent, in vivo efficacious 11β hydroxysteroid dehydrogenase type 1 (11β HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11β HSD1 activity in human adipocytes with an IC of 4.3nM and in primary human adipose tissue with an IC of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11β HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.
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http://dx.doi.org/10.1016/j.bmc.2017.04.033DOI Listing
July 2017

Influence of sub-chronic selective 11β-hydroxysteroid dehydrogenase 1 inhibition on the hypothalamic-pituitary-adrenal axis in female cynomolgus monkeys.

Eur J Pharmacol 2016 Oct 5;789:68-74. Epub 2016 Jul 5.

Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.

Inhibition of local cortisol regeneration from circulating cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. Chronic modulation of glucocorticoid homeostasis may result in hypothalamic-pituitary-adrenal (HPA) axis stimulation. HPA axis over-activation leading androgen excess would be undesirable in a therapeutic intervention designed to treat a chronic condition such as the metabolic syndrome. To address whether 11β-HSD1 inhibition would lead to excess androgens, we treated female cynomolgus monkeys with a selective inhibitor, BI 135558, for 4 weeks. Continual action of the compound over the dosing period was confirmed by constant plasma exposure, and a maintained change in urinary glucocorticoid metabolites consistent with 11β-HSD1 inhibition. No significant changes in adrenal function, as evidenced by an adrenocorticotropic hormone (ATCH) challenge, were observed. An examination of androgenic hormones revealed a slight increase in dehydroepiandrosterone sulfate (DHEA-S), while other hormones such as testosterone remained within reference values. Overall, treatment with BI 135558 in monkeys did not result in obvious over-activation of the HPA axis.
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http://dx.doi.org/10.1016/j.ejphar.2016.07.004DOI Listing
October 2016

Pharmacological characterization of the selective 11β-hydroxysteroid dehydrogenase 1 inhibitor, BI 135585, a clinical candidate for the treatment of type 2 diabetes.

Eur J Pharmacol 2015 Jan 8;746:50-5. Epub 2014 Nov 8.

Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.

To combat the increased morbidity and mortality associated with the developing diabetes epidemic new therapeutic interventions are desirable. Inhibition of intracellular cortisol generation from cortisone by blocking 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) has been shown to ameliorate the risk factors associated with the metabolic syndrome. A challenge in developing 11β-HSD1 inhibitors has been the species selectivity of small molecules, as many compounds are primate specific. Here we describe our strategy to identify potent selective 11β-HSD1 inhibitors while ensuring target engagement in key metabolic tissues, liver and fat. This strategy enabled the identification of the clinical candidate, BI 135585.
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http://dx.doi.org/10.1016/j.ejphar.2014.10.053DOI Listing
January 2015

Analysis of the transcriptome of differentiating and non-differentiating preadipocytes from rats and humans by next generation sequencing.

Mol Cell Biochem 2012 Oct 8;369(1-2):175-81. Epub 2012 Jul 8.

Target Discovery Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany.

Alongside cell lines such as 3T3-L1 cells, primary cell culture models of adipogenesis have helped in developing an understanding of the process of adipocyte recruitment and maintenance, which may lead to therapeutic advances to treat the growing epidemic of obesity. Recently, it has been demonstrated that fat cell progenitors (DFAT) established through ceiling culture of adipocytes retain an enhanced ability to undergo adipocyte differentiation compared to preadipocytes isolated from the stromal vascular fraction of adipose tissue. Clonal expansion of rat DFAT cells identified differentiation capable and incapable cell strains. To understand the mechanisms underlying these differences, comparison of their transcriptomes by next generation sequencing was performed. Two hundred seventy-eight genes with a significant fold change of 1.4 were detected as being consistently deregulated between differentiating and non-differentiating strains. Bioinformatic network analyses identified components of the extra-cellular matrix and PPARγ as important genes in this process, suggesting crosstalk between ECM and transcription factors influences differentiation. Analyses of the transcriptomes of human DFAT cells in early and late passage (non-differentiating) confirmed the importance of these pathways in maintaining an adipogenic potential.
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http://dx.doi.org/10.1007/s11010-012-1380-1DOI Listing
October 2012

Discovery of BI 99179, a potent and selective inhibitor of type I fatty acid synthase with central exposure.

Bioorg Med Chem Lett 2011 Oct 9;21(19):5924-7. Epub 2011 Aug 9.

Medicinal Chemistry, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65, D-88397 Biberach, Germany.

Based on a high-throughput screen, cyclopentanecarboxanilides were identified as a new chemotype of non-covalent inhibitors of type I fatty acid synthase (FAS). Starting from initial hits we aimed at generating a tool compound suitable for the in vivo validation of FAS as a therapeutic target. Optimisation yielded BI 99179 which is characterised by high potency, remarkably high selectivity and significant exposure (both peripheral and central) upon oral administration in rats.
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http://dx.doi.org/10.1016/j.bmcl.2011.07.083DOI Listing
October 2011

EGFL6 is increasingly expressed in human obesity and promotes proliferation of adipose tissue-derived stromal vascular cells.

Mol Cell Biochem 2010 Oct 25;343(1-2):257-69. Epub 2010 Jun 25.

Department of CardioMetabolic Diseases Research, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany.

With increasing rates of obesity driving the incidence of type 2 diabetes and cardiovascular diseases to epidemic levels, understanding of the biology of adipose tissue expansion is a focus of current research. Identification and characterization of secreted proteins of the adipose tissue could provide further insights into the function of adipose tissue and might help to therapeutically influence the development of obesity and associated metabolic disorders. In the present study, we identified human epidermal growth factor-like domain multiple-6 (EGFL6) as an adipose tissue-secreted protein. EGFL6 expression in human subcutaneous adipose tissue significantly increased with obesity and decreased after weight loss. Further, expression and secretion of EGFL6 increased with in vitro differentiation of human preadipocytes, suggesting that mature adipocytes are the main source of EGFL6. Containing epidermal growth factor (EGF)-like repeats, an Arg-Gly-Asp (RGD) integrin binding motif and a mephrin, A5 protein and receptor protein-tyrosine phosphatase mu (MAM) domain, EGFL6 was suggested to be an extra-cellular matrix protein. Recombinant human EGFL6 protein mediated cell adhesion of human adipose tissue-derived stromal vascular cells (AD-SVC) in an RGD-dependent manner. FACS analyses revealed specific binding of the protein to the cell surface of AD-SVC with the binding being predominantly mediated by the EGF-like repeats. Recombinant EGFL6 enhanced proliferation of human AD-SVC as measured by MTS assay and [(14)C]-thymidine incorporation. These results indicate that human EGFL6 is a paracrine/autocrine growth factor of adipose tissue up-regulated in obesity and potentially involved in the process of adipose tissue expansion and the development of obesity.
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http://dx.doi.org/10.1007/s11010-010-0521-7DOI Listing
October 2010

Identification of potent agonists acting at an endogenous atypical beta3-adrenoceptor state that modulate lipolysis in rodent fat cells.

Eur J Pharmacol 2008 Feb 30;580(1-2):55-62. Epub 2007 Oct 30.

Department of Metabolic Diseases, Boehringer Ingelheim Pharma GmbH & Co KG, 88397 Biberach an der Riss, Germany.

Small molecules interacting with aminergic G-protein coupled receptors represent a number of very successful drugs. G-protein coupled receptors continue to be a significant group of targets for pharmaceutical intervention, and modifying their activity through small molecules is a major focus of drug development. Previously, these small molecules could be easily fit in models, as agonists, partial agonists or antagonists. More recently, however, these lines have been blurred as it is increasingly recognized that ligands can interact with receptors in various ways. Analysis of beta-adrenoceptors has revealed that several sites or states exist for the individual receptors. The putative atypical beta(4)-adrenoceptor identified on heart and adipose tissue is now recognized as a unique beta(1)-adrenoceptor state. Similarly, a unique beta(3)-adrenoceptor state has been identified using the aryloxypropanolamine CGP-12,177 and cloned receptor systems. Here we expand upon these observations, by describing an atypical state of the beta(3)-adrenoceptor that exists endogenously in adipose tissue. Furthermore, we describe novel arylethanolamine ligands that interact with this atypical state of the beta(3)-adrenoceptor with high affinity and provide additional tools to investigate the atypical beta(3)-adrenoceptor state to determine whether it can be influenced for therapeutic purposes.
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http://dx.doi.org/10.1016/j.ejphar.2007.10.065DOI Listing
February 2008

Inhibition of fatty acid synthase prevents preadipocyte differentiation.

Biochem Biophys Res Commun 2005 Mar;328(4):1073-82

Department of Metabolic Diseases, Boehringer Ingelheim Pharma GmbH and Co KG, 88397 Biberach an der Riss, Germany.

Inhibition of fatty acid synthase (FAS) reduces food intake in rodents. As adipose tissue expresses FAS, we sought to investigate the effect of reduced FAS activity on adipocyte differentiation. FAS activity was suppressed either pharmacologically or by siRNA during differentiation of 3T3-L1 cells. Cerulenin (10 microM), triclosan (50 microM), and C75 (50 microM) reduced dramatically visible lipid droplet accumulation, while incorporation of [1-(14C)]acetate into lipids was reduced by 75%, 70%, and 90%, respectively. Additionally, the substances reduced FAS, CEBPalpha, and PPARgamma mRNA by up to 85% compared to that of control differentiated cells. Transient transfection with FAS siRNA suppressed FAS mRNA and FAS activity, and this was accompanied by reduction of CEBPalpha and PPARgamma mRNA levels, and complete prevention of lipid accumulation. CD36, a late marker of differentiation, was also reduced. Together, these results suggest that FAS generated signals may be essential to support preadipocyte differentiation.
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http://dx.doi.org/10.1016/j.bbrc.2005.01.067DOI Listing
March 2005

Characterization of the NPGP receptor and identification of a novel short mRNA isoform in human hypothalamus.

Regul Pept 2003 Mar;111(1-3):21-9

Department of Cardiovascular Research, Boehringer Ingelheim Pharma KG, 88397 Biberach, Germany.

Recently, an orphan G protein coupled receptor (GPCR) termed NPGPR was described. A shorter variant of this receptor lacking exon 1 was shown to have subnanomolar affinity for neuropeptide FF (NPFF), a pain modulatory peptide, and therefore was named NPFF(2) receptor. Here, we characterize the full-length cloned NPGPR and identify a novel short form lacking exon 2 with a differential pattern of mRNA abundance in several tissues and organs. The NPGPR is most similar to the recently cloned neuropeptide FF (NPFF) receptor which lacks exon 1, but also shows high homology to the orexin and neuropeptide Y (NPY) receptor families, two neuropeptides involved in food intake regulation. Therefore, we used binding studies to examine the interaction of NPFF, orexin and NPY with the NPGPR. [125I] NPFF was displaced by NPFF with an IC(50) of 14.7 +/- 8.8 nM, whereas [125I] Orexin B was displaced by Orexin B with an IC(50) of 415 +/- 195 nM. We conclude that orexins interact with the NPGPR and that the affinity of NPFF for NPGPR is approximately 100-fold lower than for the NPFF2 receptor. We postulate that NPGPR is a splice variant of the family of NPFF receptors and displays a binding profile different from the other members of the NPFF receptor family due to the presence of exon 1. In order to evaluate whether NPGPR levels are affected by the feeding status, we examined the mRNA level using real-time PCR in two feeding models, i.e. before and after diet-induced body weight increase as well as after chronic food restriction in rats. However, hypothalamic NPGPR mRNA was unchanged in both models. Therefore, our evidence does not support the hypothesis that NPGPR is involved in feeding regulation.
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http://dx.doi.org/10.1016/s0167-0115(02)00220-3DOI Listing
March 2003

Chronic application of MTII in a rat model of obesity results in sustained weight loss.

Obes Res 2002 Mar;10(3):182-7

Department of Cardiovascular and Metabolic Disease, Boehringer Ingelheim Pharma KG, Bierbach an der Riss, Germany.

Objective: To examine the effects of a cafeteria diet and a chronic treatment with melanocortin agonist (MTII) on mature weight-stable female rats.

Research Methods And Procedures: Ex-breeder Chbb:Thom rats (350 to 400 g) were divided into two groups: highly palatable food (HPF) and normal rat chow (RC). Both groups had ab libitum access to rat chow. The HPF group had access to chocolate bars, cookies, cheese, and nuts (approximately 20 g/d). After 21 days, the rats in each group were then divided into control and treated groups. Mini-pumps delivering saline or MTII (1 mg/kg per day) for minimally 28 days were implanted. Oxygen consumption was measured for 17 days in a second group of rats implanted with mini-pumps containing MTII (1 mg/kg per day) or saline.

Results: HPF rats ate less (<50%) rat chow than RC rats. After 20 days, the HPF group had reached a plateau and weighed significantly more (p < 0.005) than the RC group (411.7 +/- 9.3 g; n = 17 vs. 365.1 +/- 9.4 g; n = 16). HPF rats and RC rats receiving MTII reduced their pellet intake and body weight in the initial 2 weeks of treatment (day 14, RC-saline: -1.6 +/- 1.8 g; RC-MTII, -22.5 +/- 3.7 g; HPF-saline, -7.1 +/- 1.7 g; HPF-MTII, -30.7 +/- 4.8 g). Subsequently, pellet intake returned to pre-implantation values, although body weights remained reduced in both HPF and RC groups. Oxygen consumption was increased in rats treated with MTII.

Discussion: This suggests that MTII initially reduced body weight by limiting food intake; however, maintenance of weight is most likely due to increased energy expenditure under conditions of normal and highly palatable diets in mature animals.
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http://dx.doi.org/10.1038/oby.2002.28DOI Listing
March 2002