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Article: Intraoperative Autofluorescence Imaging for Parathyroid Gland Identification during Total Laryngectomy with Thyroidectomy.

Obongo Anga, Raïs / Abbaci, Muriel / Guerlain, Joanne / Breuskin, Ingrid / Casiraghi, Odile / Marhic, Alix / Benmoussa-Rebibo, Nadia / de Kermadec, Héloïse / Moya-Plana, Antoine / Temam, Stéphane / Gorphe, Philippe / Hartl, Dana M

Cancers

2023 Volume 15, Issue 3

Abstract: Objective: Hypoparathyroidism is a known complication of total laryngectomy, although parathyroid preservation and/or reimplantation are not routine. Autofluorescence is a new technique for identifying parathyroid glands intraoperatively. The aim of ... ...

Abstract	Objective: Hypoparathyroidism is a known complication of total laryngectomy, although parathyroid preservation and/or reimplantation are not routine. Autofluorescence is a new technique for identifying parathyroid glands intraoperatively. The aim of this study was to evaluate the feasibility of autofluorescence in this context. Materials and methods: A retrospective study of patients undergoing total laryngectomy/pharyngectomy with concomitant thyroidectomy using the Fluobeam Results: Eighteen patients (16 males, median age 67) underwent total laryngectomy/pharyngectomy with total thyroidectomy (n = 12) or hemithyroidectomy (n = 6). A median of 2 parathyroid glands were identified per patient. Ninety-two percent were identified by autofluorescence before visualisation. All parathyroids were reimplanted due to devascularization. Temporary hypoparathyroidism occurred in nine patients, and was permanent in one patient. After 34 months of median follow-up (range 1-49), no tumor recurrence was observed in the reimplantation sites. Conclusions: To our knowledge, this is the largest study to evaluate autofluorescence during total laryngectomy with thyroidectomy. No tumor recurrence occurred in the sites of parathyroid reimplantation.
Language	English
Publishing date	2023-01-31
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers15030875
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Article: D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II.

Gori, Sadakatali S / Thomas, Ajit G / Pal, Arindom / Wiseman, Robyn / Ferraris, Dana V / Gao, Run-Duo / Wu, Ying / Alt, Jesse / Tsukamoto, Takashi / Slusher, Barbara S / Rais, Rana

Pharmaceutics

2022 Volume 14, Issue 10

Abstract: Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) ... ...

Abstract	Glutamate carboxypeptidase-II (GCPII) is a zinc-dependent metalloenzyme implicated in numerous neurological disorders. The pharmacophoric requirements of active-site GCPII inhibitors makes them highly charged, manifesting poor pharmacokinetic (PK) properties. Herein, we describe the discovery and characterization of catechol-based inhibitors including L-DOPA, D-DOPA, and caffeic acid, with sub-micromolar potencies. Of these, D-DOPA emerged as the most promising compound, with good metabolic stability, and excellent PK properties. Orally administered D-DOPA yielded high plasma exposures (AUCplasma = 72.7 nmol·h/mL) and an absolute oral bioavailability of 47.7%. Unfortunately, D-DOPA brain exposures were low with AUCbrain = 2.42 nmol/g and AUCbrain/plasma ratio of 0.03. Given reports of isomeric inversion of D-DOPA to L-DOPA via D-amino acid oxidase (DAAO), we evaluated D-DOPA PK in combination with the DAAO inhibitor sodium benzoate and observed a >200% enhancement in both plasma and brain exposures (AUCplasma = 185 nmol·h/mL; AUCbrain = 5.48 nmol·h/g). Further, we demonstrated GCPII target engagement; orally administered D-DOPA with or without sodium benzoate caused significant inhibition of GCPII activity. Lastly, mode of inhibition studies revealed D-DOPA to be a noncompetitive, allosteric inhibitor of GCPII. To our knowledge, this is the first report of D-DOPA as a distinct scaffold for GCPII inhibition, laying the groundwork for future optimization to obtain clinically viable candidates.
Language	English
Publishing date	2022-09-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527217-2
ISSN	1999-4923
ISSN	1999-4923
DOI	10.3390/pharmaceutics14102018
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Article: Intraoperative Parathyroid Gland Identification Using Autofluorescence Imaging in Thyroid Cancer Surgery with Central Neck Dissection: Impact on Post-Operative Hypocalcemia.

Guerlain, Joanne / Breuskin, Ingrid / Abbaci, Muriel / Lamartina, Livia / Hadoux, Julien / Baudin, Eric / Al Ghuzlan, Abir / Moog, Sophie / Marhic, Alix / Villard, Adrien / Obongo, Rais / Hartl, Dana M

Cancers

2023 Volume 16, Issue 1

Abstract: Hypoparathyroidism is the most frequent complication in thyroid surgery. The aim of this study was to evaluate the impact of intraoperative parathyroid gland identification, using autofluorescence imaging, on the rate of post-operative (PO) ... ...

Abstract	Hypoparathyroidism is the most frequent complication in thyroid surgery. The aim of this study was to evaluate the impact of intraoperative parathyroid gland identification, using autofluorescence imaging, on the rate of post-operative (PO) hypoparathyroidism in thyroid cancer surgery. Patients undergoing total thyroidectomy with central neck dissection from 2018 to 2022 were included. A prospective cohort of 77 patients operated on using near-infrared autofluorescence (NIRAF+) with the Fluobeam
Language	English
Publishing date	2023-12-29
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16010182
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Article: Picture of the month. Zellweger (cerebro-hepato-renal) syndrome.

Rais Dana, J / Tunnessen, W W

Archives of pediatrics & adolescent medicine

1999 Volume 153, Issue 10, Page(s) 1105–1106

MeSH term(s)	Consanguinity ; Humans ; Infant ; Prognosis ; Zellweger Syndrome/diagnosis ; Zellweger Syndrome/genetics ; Zellweger Syndrome/physiopathology
Language	English
Publishing date	1999-10
Publishing country	United States
Document type	Case Reports ; Journal Article ; Review
ZDB-ID	1179374-0
ISSN	1538-3628 ; 1072-4710
ISSN (online)	1538-3628
ISSN	1072-4710
DOI	10.1001/archpedi.153.10.1105
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Article ; Online: Proceedings of the 14th International Newborn Brain Conference: Neonatal Neurocritical Care, seizures, and continuous aEEG and /or EEG monitoring.

Abramsky, Ramy / Acun, Ceyda / Alt, Jesse / Aly, Hany / Arad, Noa / Baak, Lisanne M / Bakalar, Dana / Balasingham, Thameya / Bammler, Theo / Benders, Manon J N L / Benitez, Diana / Boni, Elisa / Boylan, Geraldine / Campbell, Ellie / Castri, Paola / Chandrashekar, Priyanka / Chavez-Valdez, Raul / Chen, May / Chiodin, Elisabetta /

Comstock, Bryan / Damien, Janie / de Vries, Linda S / de Vries, Linda / Dickman, Jacky / Doucette, Leslie / Duckworth, Ellie / Echeverria-Palacio, Carlos / El Jalbout, Ramy / El-Dib, Mohamed / Elshibiny, Hoda / Flock, Debbie / Gallagher, Anne / Gasperoni, Enrica / Glass, Hannah / Harteman, Johanneke C / Harvey-Jones, Kelly / Hazan, Itay / Heagerty, Patrick / Inder, Terrie / Jantzie, Lauren / Juul, Sandra / Karnati, Sreenivas / Kute, Nazli / Lacaille, Helene / Lange, Frederic / Lemmers, Petra M A / Liu, Wei / Llaguno, Nathalie / Magalhães, Mauricio / Mambule, Ivan / Marandyuk, Bohdana / Marks, Kyla / Martin, Lee J / Massaro, An / Mathieson, Sean / McCaul, Melisa Carrasco / Meehan, Christopher / Meledin, Irina / Menna, Elisa / Menzato, Federica / Mintoft, Alison / Mitra, Subhabrata / Nakimuli, Annettee / Nanyunya, Carol / Norris, Georgina / Northington, Frances J / Numis, Adam / O'Reilly, Jiaqi J / Ortiz, Sandra / Padiyar, Swetha / Paquette, Natacha / Parmeggiani, Lucio / Patrizi, Silvia / Pavlidis, Elena / Pellegrin, Serena / Penn, Anna A / Petitpas, Laurence / Pinchefsky, Elana / Ponta, Alessandra / Puthuraya, Jacopo Proietti Subhash / Rais, Rana / Robertson, Nicola J / Rodrigues, Daniela / Salandin, Michela / Salzbank, Jacquelyn / Sánchez, Lilia / Schalij, Nienke / Serrano-Tabares, Carolina / Shany, Eilon / Staffler, Alex / Steggerda, Sylke / Tachtsidis, Ilias / Tann, Cally / Tataranno, Maria Luisa / Trabatti, Chiara / Tremblay, Julie / Tromp, Selma / Tucker, Katie / Turnbill, Victoria / Vacher, Claire-Marie / van Bel, Frank / van der Aa, Niek E / Van Meurs, Krisa / Van Steenis, Andrea / van Wyk, Linda / Vannasing, Phetsamone / Variane, Gabriel / Verma, Vinita / Voldal, Emily / Wagenaar, Nienke / Wu, Yvonne / Wustoff, Courtney

Journal of neonatal-perinatal medicine

2023 Volume 16, Issue s1, Page(s) S33–S62

Language	English
Publishing date	2023-08-19
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2435387-5
ISSN	1878-4429 ; 1934-5798
ISSN (online)	1878-4429
ISSN	1934-5798
DOI	10.3233/NPM-239003
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Article ; Online: D-Amino acid oxidase inhibitors based on the 5-hydroxy-1,2,4-triazin-6(1H)-one scaffold.

Hin, Niyada / Duvall, Bridget / Berry, James F / Ferraris, Dana V / Rais, Rana / Alt, Jesse / Rojas, Camilo / Slusher, Barbara S / Tsukamoto, Takashi

Bioorganic & medicinal chemistry letters

2016 Volume 26, Issue 8, Page(s) 2088–2091

Abstract: A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of d-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO ...

Abstract	A series of 3-substituted 5-hydroxy-1,2,4-triazin-6(1H)-one derivatives were designed and synthesized as a new class of d-amino acid oxidase (DAAO) inhibitors. Some of the newly synthesized derivatives showed potent inhibitory activity against human DAAO with IC50 values in the nanomolar range. Among them, 6-hydroxy-3-phenethyl-1,2,4-triazin-5(2H)-one 6b and 3-((6-fluoronaphthalen-2-yl)methylthio)-6-hydroxy-1,2,4-triazin-5(2H)-one 6m were found to be metabolically stable in mouse liver microsomes. In addition, compound 6b was found to be orally available in mice and able to enhance plasma d-serine levels following its co-administration with d-serine compared to the oral administration of d-serine alone.
MeSH term(s)	Animals ; D-Amino-Acid Oxidase/antagonists & inhibitors ; D-Amino-Acid Oxidase/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/metabolism ; Enzyme Inhibitors/pharmacology ; Humans ; Mice ; Microsomes, Liver/chemistry ; Microsomes, Liver/metabolism ; Molecular Structure ; Serine/blood ; Structure-Activity Relationship ; Triazines/chemistry ; Triazines/metabolism ; Triazines/pharmacology
Chemical Substances	5-hydroxy-1,2,4-triazin-6(1H)-one ; Enzyme Inhibitors ; Triazines ; Serine (452VLY9402) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2016-02-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1063195-1
ISSN	1464-3405 ; 0960-894X
ISSN (online)	1464-3405
ISSN	0960-894X
DOI	10.1016/j.bmcl.2016.02.068
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Article ; Online: D-Amino-Acid Oxidase Inhibition Increases D-Serine Plasma Levels in Mouse But not in Monkey or Dog.

Rojas, Camilo / Alt, Jesse / Ator, Nancy A / Thomas, Ajit G / Wu, Ying / Hin, Niyada / Wozniak, Krystyna / Ferraris, Dana / Rais, Rana / Tsukamoto, Takashi / Slusher, Barbara S

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology

2016 Volume 41, Issue 6, Page(s) 1610–1619

Abstract: D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to ...

Abstract	D-serine has been shown to improve positive, negative, and cognitive symptoms when used as add-on therapy for the treatment of schizophrenia. However, D-serine has to be administered at high doses to observe clinical effects. This is thought to be due to D-serine undergoing oxidation by D-amino-acid oxidase (DAAO) before it reaches the brain. Consequently, co-administration of D-serine with a DAAO inhibitor could be a way to lower the D-serine dose required to treat schizophrenia. Early studies in rodents to evaluate this hypothesis showed that concomitant administration of structurally distinct DAAO inhibitors with D-serine enhanced plasma and brain D-serine levels in rodents compared with administration of D-serine alone. In the present work we used three potent DAAO inhibitors and confirmed previous results in mice. In a follow-up effort, we evaluated plasma D-serine levels in monkeys after oral administration of D-serine in the presence or absence of these DAAO inhibitors. Even though the compounds reached steady state plasma concentrations exceeding their Ki values by >60-fold, plasma D-serine levels remained the same as those in the absence of DAAO inhibitors. Similar results were obtained with dogs. In summary, in contrast to rodents, DAAO inhibition in monkeys and dogs did not influence the exposure to exogenously administered D-serine. Results could be due to differences in D-serine metabolism and/or clearance mechanisms and suggest that the role of DAAO in the metabolism of D-serine is different across species. These data provide caution regarding the utility of DAAO inhibition for patients with schizophrenia.
MeSH term(s)	Animals ; D-Amino-Acid Oxidase/antagonists & inhibitors ; D-Amino-Acid Oxidase/metabolism ; Dogs ; Isoxazoles/pharmacology ; Male ; Mice ; Papio hamadryas ; Serine/blood ; Species Specificity
Chemical Substances	5-chlorobenzo(d)isoxazol-3-ol ; Isoxazoles ; Serine (452VLY9402) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2016-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639471-1
ISSN	1740-634X ; 0893-133X
ISSN (online)	1740-634X
ISSN	0893-133X
DOI	10.1038/npp.2015.319
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Article ; Online: 6-Hydroxy-1,2,4-triazine-3,5(2H,4H)-dione Derivatives as Novel D-Amino Acid Oxidase Inhibitors.

Hin, Niyada / Duvall, Bridget / Ferraris, Dana / Alt, Jesse / Thomas, Ajit G / Rais, Rana / Rojas, Camilo / Wu, Ying / Wozniak, Krystyna M / Slusher, Barbara S / Tsukamoto, Takashi

Journal of medicinal chemistry

2015 Volume 58, Issue 18, Page(s) 7258–7272

Abstract: A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of D-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors, with IC50 values in the double-digit ... ...

Abstract	A series of 2-substituted 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione derivatives were synthesized as inhibitors of D-amino acid oxidase (DAAO). Many compounds in this series were found to be potent DAAO inhibitors, with IC50 values in the double-digit nanomolar range. The 6-hydroxy-1,2,4-triazine-3,5(2H,4H)-dione pharmacophore appears metabolically resistant to O-glucuronidation unlike other structurally related DAAO inhibitors. Among them, 6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione 11h was found to be selective over a number of targets and orally available in mice. Furthermore, oral coadministration of D-serine with 11h enhanced the plasma levels of D-serine in mice compared to the oral administration of D-serine alone, demonstrating its ability to serve as a pharmacoenhancer of D-serine.
MeSH term(s)	Animals ; Biological Availability ; Cell Line ; D-Amino-Acid Oxidase/antagonists & inhibitors ; Drug Interactions ; Humans ; Male ; Mice ; Models, Molecular ; Protein Binding ; Receptors, N-Methyl-D-Aspartate/agonists ; Serine/blood ; Serine/chemistry ; Serine/pharmacology ; Stereoisomerism ; Structure-Activity Relationship ; Triazines/chemistry ; Triazines/pharmacokinetics ; Triazines/pharmacology
Chemical Substances	6-hydroxy-2-(naphthalen-1-ylmethyl)-1,2,4-triazine-3,5(2H,4H)-dione ; Receptors, N-Methyl-D-Aspartate ; Triazines ; Serine (452VLY9402) ; D-Amino-Acid Oxidase (EC 1.4.3.3)
Language	English
Publishing date	2015-09-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.5b00482
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Article ; Online: Discovery of 6-Diazo-5-oxo-l-norleucine (DON) Prodrugs with Enhanced CSF Delivery in Monkeys: A Potential Treatment for Glioblastoma.

Rais, Rana / Jančařík, Andrej / Tenora, Lukáš / Nedelcovych, Michael / Alt, Jesse / Englert, Judson / Rojas, Camilo / Le, Anne / Elgogary, Amira / Tan, Jessica / Monincová, Lenka / Pate, Kelly / Adams, Robert / Ferraris, Dana / Powell, Jonathan / Majer, Pavel / Slusher, Barbara S

Journal of medicinal chemistry

2016 Volume 59, Issue 18, Page(s) 8621–8633

Abstract: The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine ... ...

Abstract	The glutamine antagonist 6-diazo-5-oxo-l-norleucine (DON, 1) has shown robust anticancer efficacy in preclinical and clinical studies, but its development was halted due to marked systemic toxicities. Herein we demonstrate that DON inhibits glutamine metabolism and provides antitumor efficacy in a murine model of glioblastoma, although toxicity was observed. To enhance DON's therapeutic index, we utilized a prodrug strategy to increase its brain delivery and limit systemic exposure. Unexpectedly, simple alkyl ester-based prodrugs were ineffective due to chemical instability cyclizing to form a unique diazo-imine. However, masking both DON's amine and carboxylate functionalities imparted sufficient chemical stability for biological testing. While these dual moiety prodrugs exhibited rapid metabolism in mouse plasma, several provided excellent stability in monkey and human plasma. The most stable compound (5c, methyl-POM-DON-isopropyl-ester) was evaluated in monkeys, where it achieved 10-fold enhanced cerebrospinal fluid to plasma ratio versus DON. This strategy may provide a path to DON utilization in glioblastoma multiforme patients.
MeSH term(s)	Animals ; Antimetabolites, Antineoplastic/cerebrospinal fluid ; Antimetabolites, Antineoplastic/therapeutic use ; Brain Neoplasms/drug therapy ; Brain Neoplasms/metabolism ; Diazooxonorleucine/cerebrospinal fluid ; Diazooxonorleucine/therapeutic use ; Female ; Glioblastoma/drug therapy ; Glioblastoma/metabolism ; Glutamine/metabolism ; Haplorhini ; Humans ; Mice ; Mice, Nude ; Prodrugs/pharmacokinetics ; Prodrugs/therapeutic use
Chemical Substances	Antimetabolites, Antineoplastic ; Prodrugs ; Diazooxonorleucine (03J0H273KZ) ; Glutamine (0RH81L854J)
Language	English
Publishing date	2016-09-06
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.6b01069
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Article ; Online: Unprecedented Binding Mode of Hydroxamate-Based Inhibitors of Glutamate Carboxypeptidase II: Structural Characterization and Biological Activity.

Novakova, Zora / Wozniak, Krystyna / Jancarik, Andrej / Rais, Rana / Wu, Ying / Pavlicek, Jiri / Ferraris, Dana / Havlinova, Barbora / Ptacek, Jakub / Vavra, Jan / Hin, Niyada / Rojas, Camilo / Majer, Pavel / Slusher, Barbara S / Tsukamoto, Takashi / Barinka, Cyril

Journal of medicinal chemistry

2016 Volume 59, Issue 10, Page(s) 4539–4550

Abstract: Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity ...

Abstract	Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket. This unique binding mode provides a mechanistic explanation for the structure-activity relationship data, most notably the lack of enantiospecificity and the tolerance for bulky/hydrophobic functions as substituents of a canonical glutarate moiety. The in vivo pharmacokinetics profile of one of the inhibitors will be presented along with analgesic efficacy data from the rat chronic constrictive injury model of neuropathic pain.
MeSH term(s)	Antigens, Surface/metabolism ; Dose-Response Relationship, Drug ; Enzyme Inhibitors/chemical synthesis ; Enzyme Inhibitors/chemistry ; Enzyme Inhibitors/pharmacology ; Glutamate Carboxypeptidase II/antagonists & inhibitors ; Glutamate Carboxypeptidase II/metabolism ; Humans ; Hydroxamic Acids/chemical synthesis ; Hydroxamic Acids/chemistry ; Hydroxamic Acids/pharmacology ; Models, Molecular ; Molecular Structure ; Structure-Activity Relationship
Chemical Substances	Antigens, Surface ; Enzyme Inhibitors ; Hydroxamic Acids ; FOLH1 protein, human (EC 3.4.17.21) ; Glutamate Carboxypeptidase II (EC 3.4.17.21)
Language	English
Publishing date	2016-04-25
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.5b01806
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