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Article ; Online: Animal models of chronic and recurrent Pseudomonas aeruginosa lung infection: significance of macrolide treatment.

Thomsen, Kim / Kobayashi, Osamu / Kishi, Kenji / Shirai, Ryo / Østrup Jensen, Peter / Heydorn, Arne / Hentzer, Morten / Calum, Henrik / Christophersen, Lars / Høiby, Niels / Moser, Claus

APMIS : acta pathologica, microbiologica, et immunologica Scandinavica

2021 Volume 130, Issue 7, Page(s) 458–476

Abstract: Animal models of human diseases are invaluable and inevitable elements in identifying and testing novel treatments for serious diseases, including severe infections. Planning and conducting investigator-initiated human trials are generally accepted as ... ...

Abstract	Animal models of human diseases are invaluable and inevitable elements in identifying and testing novel treatments for serious diseases, including severe infections. Planning and conducting investigator-initiated human trials are generally accepted as being enormously challenging. In contrast, it is often underestimated how much planning, including background and modifying experiments, is needed to establish a relevant infectious disease animal model. However, representative animal infectious models, well designed to test generated hypotheses, are useful to improve our understanding of pathogenesis, virulence factors and host response and to identify novel treatment candidates and therapeutic strategies. Such results can subsequently proceed to clinical testing if suitable. The present review aims at presenting all the pulmonary Pseudomonas aeruginosa infectious models we have knowledge of and the detailed descriptions of established animal models in our laboratory focusing on macrolide therapy are presented.
MeSH term(s)	Animals ; Anti-Bacterial Agents/therapeutic use ; Cystic Fibrosis/drug therapy ; Disease Models, Animal ; Humans ; Lung ; Macrolides/pharmacology ; Macrolides/therapeutic use ; Pseudomonas Infections/drug therapy ; Pseudomonas aeruginosa/physiology
Chemical Substances	Anti-Bacterial Agents ; Macrolides
Language	English
Publishing date	2021-07-21
Publishing country	Denmark
Document type	Journal Article ; Review
ZDB-ID	93340-5
ISSN	1600-0463 ; 0903-4641
ISSN (online)	1600-0463
ISSN	0903-4641
DOI	10.1111/apm.13161
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Article: Protection of Primary Dopaminergic Midbrain Neurons by GPR139 Agonists Supports Different Mechanisms of MPP(+) and Rotenone Toxicity.

Bayer Andersen, Kirsten / Leander Johansen, Jens / Hentzer, Morten / Smith, Garrick Paul / Dietz, Gunnar P H

Frontiers in cellular neuroscience

2016 Volume 10, Page(s) 164

Abstract: The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we ... ...

Abstract	The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson's disease (PD) models and potential for GPR139 agonists in neuroprotection.
Language	English
Publishing date	2016-06-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2452963-1
ISSN	1662-5102
ISSN	1662-5102
DOI	10.3389/fncel.2016.00164
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Article ; Online: Design and Synthesis of Pyrrolo[2,3-

Williamson, Douglas S / Smith, Garrick P / Mikkelsen, Gitte K / Jensen, Thomas / Acheson-Dossang, Pamela / Badolo, Lassina / Bedford, Simon T / Chell, Victoria / Chen, I-Jen / Dokurno, Pawel / Hentzer, Morten / Newland, Samantha / Ray, Stuart C / Shaw, Terry / Surgenor, Allan E / Terry, Lindsey / Wang, Yikang / Christensen, Kenneth V

Journal of medicinal chemistry

2021 Volume 64, Issue 14, Page(s) 10312–10332

Abstract: Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3- ...

Abstract	Inhibitors of leucine-rich repeat kinase 2 (LRRK2) and mutants, such as G2019S, have potential utility in Parkinson's disease treatment. Fragment hit-derived pyrrolo[2,3-
MeSH term(s)	Checkpoint Kinase 1/chemistry ; Checkpoint Kinase 1/metabolism ; Crystallography, X-Ray ; Dose-Response Relationship, Drug ; Drug Design ; HEK293 Cells ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Models, Molecular ; Molecular Structure ; Protein Kinase Inhibitors/chemical synthesis ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/chemical synthesis ; Pyrimidines/chemistry ; Pyrimidines/pharmacology ; Pyrroles/chemical synthesis ; Pyrroles/chemistry ; Pyrroles/pharmacology ; Structure-Activity Relationship
Chemical Substances	Protein Kinase Inhibitors ; Pyrimidines ; Pyrroles ; Pyrrolo(2,3-d)pyrimidine ; CHEK1 protein, human (EC 2.7.11.1) ; Checkpoint Kinase 1 (EC 2.7.11.1) ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1)
Language	English
Publishing date	2021-06-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.1c00720
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Article ; Online: High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139.

Wang, Jia / Zhu, Lin-yun / Liu, Qing / Hentzer, Morten / Smith, Garrick Paul / Wang, Ming-wei

Acta pharmacologica Sinica

2015 Volume 36, Issue 7, Page(s) 874–878

Abstract: Aim: To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules.: Methods: Calcium mobilization assays were used to identify initial hits and for subsequent ... ...

Abstract	Aim: To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules. Methods: Calcium mobilization assays were used to identify initial hits and for subsequent confirmation studies. Results: Five small molecule antagonists, representing 4 different scaffolds, were identified following high-throughput screening of 16 000 synthetic compounds. Conclusion: The findings provide important tools for further study of this orphan G-protein coupled receptor.
MeSH term(s)	Animals ; CHO Cells ; Calcium/metabolism ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/methods ; High-Throughput Screening Assays/methods ; Humans ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/metabolism ; Receptors, G-Protein-Coupled/antagonists & inhibitors ; Receptors, G-Protein-Coupled/metabolism
Chemical Substances	GPR139 protein, human ; Nerve Tissue Proteins ; Receptors, G-Protein-Coupled ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2015-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1360774-1
ISSN	1745-7254 ; 0253-9756 ; 1671-4083
ISSN (online)	1745-7254
ISSN	0253-9756 ; 1671-4083
DOI	10.1038/aps.2015.12
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Article: Pharmacological inhibition of quorum sensing for the treatment of chronic bacterial infections.

Hentzer, Morten / Givskov, Michael

The Journal of clinical investigation

2003 Volume 112, Issue 9, Page(s) 1300–1307

Abstract: Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. The discovery of ... ...

Abstract	Traditional treatment of infectious diseases is based on compounds that aim to kill or inhibit bacterial growth. A major concern with this approach is the frequently observed development of resistance to antimicrobial compounds. The discovery of bacterial-communication systems (quorum-sensing systems), which orchestrate important temporal events during the infection process, has afforded a novel opportunity to ameliorate bacterial infection by means other than growth inhibition. Compounds able to override bacterial signaling are present in nature. Herein we discuss the known signaling mechanisms and potential antipathogenic drugs that specifically target quorum-sensing systems in a manner unlikely to pose a selective pressure for the development of resistant mutants.
MeSH term(s)	4-Butyrolactone/analogs & derivatives ; 4-Butyrolactone/antagonists & inhibitors ; 4-Butyrolactone/physiology ; Animals ; Anti-Bacterial Agents/pharmacology ; Bacterial Infections/drug therapy ; Biofilms ; Chronic Disease ; Furans/pharmacology ; Humans ; Signal Transduction/drug effects
Chemical Substances	Anti-Bacterial Agents ; Furans ; homoserine lactone (1192-20-7) ; 4-Butyrolactone (OL659KIY4X)
Language	English
Publishing date	2003-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI20074
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Article ; Online: The design and SAR of a novel series of 2-aminopyridine based LRRK2 inhibitors.

Smith, Garrick P / Badolo, Lassina / Chell, Victoria / Chen, I-Jen / Christensen, Kenneth Vielsted / David, Laurent / Daechsel, Justus Alfred / Hentzer, Morten / Herzig, Martin Christian / Mikkelsen, Gitte Kobberøe / Watson, Stephen P / Williamson, Douglas S

Bioorganic & medicinal chemistry letters

2017 Volume 27, Issue 18, Page(s) 4500–4505

Abstract: Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed ... ...

Abstract	Leucine-rich repeat kinase 2 (LRRK2) has attracted considerable interest as a therapeutic target for the treatment of Parkinson's disease. Compounds derived from a 2-aminopyridine screening hit were optimised using a LRRK2 homology model based on mixed lineage kinase 1 (MLK1), such that a 2-aminopyridine-based lead molecule 45, with in vivo activity, was identified.
MeSH term(s)	Aminopyridines/chemical synthesis ; Aminopyridines/chemistry ; Aminopyridines/pharmacology ; Animals ; Dogs ; Dose-Response Relationship, Drug ; Drug Design ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/antagonists & inhibitors ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/metabolism ; Madin Darby Canine Kidney Cells/drug effects ; Microsomes, Liver/drug effects ; Microsomes, Liver/metabolism ; Molecular Structure ; Rats ; Structure-Activity Relationship
Chemical Substances	Aminopyridines ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; alpha-aminopyridine (WSX981HEWU)
Language	English
Publishing date	2017--15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2017.07.072
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Article ; Online: Abnormal visual gain control in a Parkinson's disease model.

Afsari, Farinaz / Christensen, Kenneth V / Smith, Garrick Paul / Hentzer, Morten / Nippe, Olivia M / Elliott, Christopher J H / Wade, Alex R

Human molecular genetics

2014 Volume 23, Issue 17, Page(s) 4465–4478

Abstract: Our understanding of Parkinson's disease (PD) has been revolutionized by the discovery of disease-causing genetic mutations. The most common of these is the G2019S mutation in the LRRK2 kinase gene, which leads to increased kinase activity. However, the ... ...

Abstract	Our understanding of Parkinson's disease (PD) has been revolutionized by the discovery of disease-causing genetic mutations. The most common of these is the G2019S mutation in the LRRK2 kinase gene, which leads to increased kinase activity. However, the link between increased kinase activity and PD is unclear. Previously, we showed that dopaminergic expression of the human LRRK2-G2019S transgene in flies led to an activity-dependent loss of vision in older animals and we hypothesized that this may have been preceded by a failure to regulate neuronal activity correctly in younger animals. To test this hypothesis, we used a sensitive measure of visual function based on frequency-tagged steady-state visually evoked potentials. Spectral analysis allowed us to identify signals from multiple levels of the fly visual system and wild-type visual response curves were qualitatively similar to those from human cortex. Dopaminergic expression of hLRRK2-G2019S increased contrast sensitivity throughout the retinal network. To test whether this was due to increased kinase activity, we fed Drosophila with kinase inhibitors targeted at LRRK2. Contrast sensitivity in both day 1 and day 14 flies was normalized by a novel LRRK2 kinase inhibitor 'BMPPB-32'. Biochemical and cellular assays suggested that BMPPB-32 would be a more specific kinase inhibitor than LRRK2-IN-1. We confirmed this in vivo, finding that dLRRK(-) null flies show large off-target effects with LRRK2-IN-1 but not BMPPB-32. Our data link the increased Kinase activity of the G2019S-LRRK2 mutation to neuronal dysfunction and demonstrate the power of the Drosophila visual system in assaying the neurological effects of genetic diseases and therapies.
MeSH term(s)	Animals ; Contrast Sensitivity/drug effects ; Disease Models, Animal ; Drosophila melanogaster/physiology ; Evoked Potentials, Visual/drug effects ; Humans ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; Models, Biological ; Mutation/genetics ; Neurons/drug effects ; Neurons/metabolism ; Parkinson Disease/physiopathology ; Perceptual Masking ; Photoreceptor Cells, Invertebrate/drug effects ; Photoreceptor Cells, Invertebrate/metabolism ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/genetics ; Signal Transduction/drug effects ; Vision, Ocular/drug effects ; Vision, Ocular/physiology
Chemical Substances	Protein Kinase Inhibitors ; LRRK2 protein, human (EC 2.7.11.1) ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (EC 2.7.11.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2014-04-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108742-0
ISSN	1460-2083 ; 0964-6906
ISSN (online)	1460-2083
ISSN	0964-6906
DOI	10.1093/hmg/ddu159
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Article ; Online: Discovery of a potent and brain penetrant mGluR5 positive allosteric modulator.

Ritzén, Andreas / Sindet, Rikke / Hentzer, Morten / Svendsen, Nannette / Brodbeck, Robbin M / Bundgaard, Christoffer

Bioorganic & medicinal chemistry letters

2009 Volume 19, Issue 12, Page(s) 3275–3278

Abstract: This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral ... ...

Abstract	This Letter describes the discovery of a novel series of mGluR5 positive allosteric modulators (PAMs). The lead compound, 11c, exhibits excellent potency (EC(50)=30 nM) in vitro, and reaches high brain levels in both rats and mice after oral administration.
MeSH term(s)	Administration, Oral ; Alkynes/chemistry ; Alkynes/pharmacology ; Allosteric Regulation ; Animals ; Brain/metabolism ; Drug Discovery ; Heterocyclic Compounds/chemistry ; Heterocyclic Compounds/pharmacology ; Mice ; Rats ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate/agonists ; Structure-Activity Relationship
Chemical Substances	Alkynes ; Grm5 protein, mouse ; Grm5 protein, rat ; Heterocyclic Compounds ; Receptor, Metabotropic Glutamate 5 ; Receptors, Metabotropic Glutamate
Language	English
Publishing date	2009-06-15
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2009.04.095
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Article: Quorum sensing : a novel target for the treatment of biofilm infections.

Hentzer, Morten / Eberl, Leo / Nielsen, John / Givskov, Michael

BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy

2003 Volume 17, Issue 4, Page(s) 241–250

Abstract: Present-day treatment of chronic infections is based on compounds that aim to kill or inhibit growth of bacteria. Two problems are recognised to be intrinsically associated with this approach: (i) the frequently observed development of resistance to ... ...

Abstract	Present-day treatment of chronic infections is based on compounds that aim to kill or inhibit growth of bacteria. Two problems are recognised to be intrinsically associated with this approach: (i) the frequently observed development of resistance to antimicrobial compounds; and (ii) the fact that all therapeutics are considerably less effective on bacteria growing as biofilms when compared with planktonic cells. The latter point is of particular importance as evidence has accumulated over the past few years that most chronic bacterial infections involve biofilms. The discovery of bacterial communication systems (quorum sensing systems) in Gram-negative bacteria which are believed to orchestrate important temporal events during the infectious process, including the production of virulence factors and the formation of biofilms, has afforded a novel opportunity to control the activity of infecting bacteria by other means than interfering with growth. Compounds that interfere with communication systems are present in nature. Such compounds should not only specifically attenuate the production of virulence factors but should also affect biofilm formation in a manner that is unlikely to pose a selective pressure for the development of resistant mutants.
MeSH term(s)	Animals ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/therapeutic use ; Biofilms/drug effects ; Biofilms/growth & development ; Pseudomonas Infections/drug therapy ; Signal Transduction/drug effects ; Structure-Activity Relationship ; Technology, Pharmaceutical/trends
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2003-07-10
Publishing country	New Zealand
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1364202-9
ISSN	1179-190X ; 1173-8804
ISSN (online)	1179-190X
ISSN	1173-8804
DOI	10.2165/00063030-200317040-00003
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Article ; Online: Hit-to-lead investigation of a series of novel combined dopamine D2 and muscarinic M1 receptor ligands with putative antipsychotic and pro-cognitive potential.

Sams, Anette Graven / Larsen, Krestian / Mikkelsen, Gitte Kobberøe / Hentzer, Morten / Christoffersen, Claus Tornby / Jensen, Klaus Gjervig / Frederiksen, Kristen / Bang-Andersen, Benny

Bioorganic & medicinal chemistry letters

2012 Volume 22, Issue 15, Page(s) 5134–5140

Abstract: We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy ... ...

Abstract	We describe the discovery of a series of compounds based on 1-{3-[4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidin-1-yl]-propyl}-3,4-dihydro-1H-quinolin-2-one (3), showing combined D(2) receptor affinity and M(1) receptor agonism. Based on a strategy of controlling logP, we herein describe a hit-to-lead investigation with the aim of retaining the combined D(2)/M(1) profile, while removing the propensity of the compounds to inhibit the hERG channel, as well as at obtaining acceptable pharmacokinetic properties. Although a SAR was evident for all four parameters in question, it was not possible to separate hERG channel inhibition and D(2) receptor affinity by this effort; whilst it was feasible to obtain compounds with M(1) receptor agonism, acceptable clearance, and weak hERG inhibition.
MeSH term(s)	Antipsychotic Agents/chemical synthesis ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/pharmacokinetics ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels/antagonists & inhibitors ; Ether-A-Go-Go Potassium Channels/metabolism ; Half-Life ; Humans ; Ligands ; Microsomes, Liver/metabolism ; Quinolones/chemical synthesis ; Quinolones/chemistry ; Quinolones/pharmacokinetics ; Receptor, Muscarinic M1/agonists ; Receptor, Muscarinic M1/metabolism ; Receptors, Dopamine D2/agonists ; Receptors, Dopamine D2/metabolism ; Structure-Activity Relationship
Chemical Substances	Antipsychotic Agents ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels ; KCNH2 protein, human ; Ligands ; Quinolones ; Receptor, Muscarinic M1 ; Receptors, Dopamine D2
Language	English
Publishing date	2012-08-01
Publishing country	England
Document type	Journal Article
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2012.05.048
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