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1

Article

Structures of ClpP in complex with acyldepsipeptide antibiotics reveal its activation mechanism

Park, Eun Young ; Rübsamen-Schaeff, Helga ; Lee, Byung-Gil ; [et al.]

2010

ISSN: 1545-9993

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Language: English

In: Nature structural & molecular biology, 2010-04, Vol.17 (4), p.471-478

Description: Clp-family proteins are prototypes for studying the mechanism of ATP-dependent proteases because the proteolytic activity of the ClpP core is tightly regulated by activating Clp-ATPases. Nonetheless, the proteolytic activation mechanism has remained elusive because of the lack of a complex structure. Acyldepsipeptides (ADEPs), a recently discovered class of antibiotics, activate and disregulate ClpP. Here we have elucidated the structural changes underlying the ClpP activation process by ADEPs. We present the structures of Bacillus subtilis ClpP alone and in complex with ADEP1 and ADEP2. The structures show the closed-to-open-gate transition of the ClpP N-terminal segments upon activation as well as conformational changes restricted to the upper portion of ClpP. The direction of the conformational movement and the hydrophobic clustering that stabilizes the closed structure are markedly different from those of other ATP-dependent proteases, providing unprecedented insights into the activation of ClpP.

Subject(s): Adenosine triphosphatase ; Anti-Bacterial Agents - chemistry ; Antibiotics ; Bacillus subtilis - chemistry ; Bacteria ; Cellular proteins ; Endopeptidase Clp - chemistry ; Endopeptidase Clp - metabolism ; Escherichia coli Proteins - chemistry ; Escherichia coli Proteins - metabolism ; Health aspects ; Peptides ; Peptides - chemistry ; Physiological aspects ; Proteases ; Protein Conformation ; Proteins ; Research ; Structure ; Usage

ISSN: 1545-9993

E-ISSN: 1545-9985

DOI: 10.1038/nsmb.1787

Source: Academic Search Ultimate

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URL: https://www.ncbi.nlm.nih.gov/pubmed/20305655$$D View this record in MEDLINE/PubMed

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2

Article

Dysregulation of bacterial proteolytic machinery by a new class of antibiotics

Brötz-Oesterhelt, Heike ; Beyer, Dieter ; Kroll, Hein-Peter ; [et al.]

2005

ISSN: 1078-8956

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Language: English

In: Nature medicine, 2005-10, Vol.11 (10), p.1082-1087

Description: Here we show that a new class of antibiotics-acyldepsipeptides-has antibacterial activity against Gram-positive bacteria in vitro and in several rodent models of bacterial infection. The acyldepsipeptides are active against isolates that are resistant to antibiotics in clinical application, implying a new target, which we identify as ClpP, the core unit of a major bacterial protease complex. ClpP is usually tightly regulated and strictly requires a member of the family of Clp-ATPases and often further accessory proteins for proteolytic activation. Binding of acyldepsipeptides to ClpP eliminates these safeguards. The acyldepsipeptide-activated ClpP core is capable of proteolytic degradation in the absence of the regulatory Clp-ATPases. Such uncontrolled proteolysis leads to inhibition of bacterial cell division and eventually cell death.

Subject(s): Animals ; Anti-Bacterial Agents - classification ; Anti-Bacterial Agents - pharmacokinetics ; Anti-Bacterial Agents - pharmacology ; Anti-Bacterial Agents - toxicity ; Bacillus subtilis - drug effects ; Bacteria ; Bacteria - drug effects ; Bacteria - enzymology ; Bacteria - metabolism ; Depsipeptides - metabolism ; Depsipeptides - pharmacokinetics ; Depsipeptides - pharmacology ; Depsipeptides - toxicity ; Drug Resistance, Multiple, Bacterial ; Endopeptidase Clp - metabolism ; Escherichia coli - drug effects ; Escherichia coli Proteins - metabolism ; Female ; Mice ; Molecular Structure ; Mutation ; Pneumococcal Infections - drug therapy ; Pneumococcal Infections - microbiology ; Protein Binding ; Protein Processing, Post-Translational ; Rats ; Rats, Wistar ; Sepsis - drug therapy ; Sepsis - microbiology

ISSN: 1078-8956

E-ISSN: 1546-170X

DOI: 10.1038/nm1306

Source: Academic Search Ultimate

Source: Nature Journals Online

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URL: https://www.ncbi.nlm.nih.gov/pubmed/16200071$$D View this record in MEDLINE/PubMed

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3

Article

Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases

Bärfacker, Lars ; Kuhl, Alexander ; Hillisch, Alexander ; [et al.]

2012

ISSN: 1860-7179

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Language: English

In: ChemMedChem, 2012-08, Vol.7 (8), p.1385-1403

Description: Aldosterone is a hormone that exerts manifold deleterious effects on the kidneys, blood vessels, and heart which can lead to pathophysiological consequences. Inhibition of the mineralocorticoid receptor (MR) is a proven therapeutic concept for the management of associated diseases. Use of the currently marketed MR antagonists spironolactone and eplerenone is restricted, however, due to a lack of selectivity in spironolactone and the lower potency and efficacy of eplerenone. Several pharmaceutical companies have implemented programs to identify drugs that overcome the known liabilities of steroidal MR antagonists. Herein we disclose an extended SAR exploration starting from cyano‐1,4‐dihydropyridines that were identified by high‐throughput screening. Our efforts led to the identification of a dihydronaphthyridine, BAY 94‐8862, which is a potent, selective, and orally available nonsteroidal MR antagonist currently under investigation in a clinical phase II trial. MR activation kept at BAY: Inappropriate activation of the mineralocorticoid receptor by aldosterone or cortisol contributes to the development of cardiovascular diseases. BAY 94‐8862, antagonizing these effects, was identified in a lead optimization program and is currently being investigated in a phase II clinical trial for the treatment of chronic heart failure patients with renal impairment.

Subject(s): Animals ; BAY 94-8862 ; Binding Sites ; cardiorenal disease ; Care and treatment ; Chronic Disease ; Computer Simulation ; Drug Evaluation, Preclinical ; Heart failure ; Heart Failure - complications ; Heart Failure - drug therapy ; Humans ; Kidney Diseases - complications ; Kidney Diseases - drug therapy ; Mineralocorticoid Receptor Antagonists - chemical synthesis ; Mineralocorticoid Receptor Antagonists - chemistry ; Mineralocorticoid Receptor Antagonists - therapeutic use ; MR antagonists ; Naphthyridines - chemical synthesis ; Naphthyridines - chemistry ; Naphthyridines - therapeutic use ; natriuresis ; Nitriles ; Potassium - urine ; Protein Structure, Tertiary ; Rats ; Receptors, Mineralocorticoid - chemistry ; Receptors, Mineralocorticoid - metabolism ; Sodium - urine ; Spironolactone ; Steroids

ISSN: 1860-7179

E-ISSN: 1860-7187

DOI: 10.1002/cmdc.201200081

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Source: Wiley-Blackwell Full Collection 2014

URL: https://www.ncbi.nlm.nih.gov/pubmed/22791416$$D View this record in MEDLINE/PubMed

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4

Article

Cover Picture: Discovery of BAY 94-8862: A Nonsteroidal Antagonist of the Mineralocorticoid Receptor for the Treatment of Cardiorenal Diseases (ChemMedChem 8/2012)

Bärfacker, Lars ; Kuhl, Alexander ; Hillisch, Alexander ; [et al.]

2012

ISSN: 1860-7179

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Language: English

In: ChemMedChem, 2012-08, Vol.7 (8), p.1301-1301

Description: Keywords: BAY 94-8862; cardiorenal disease; heart failure; MR antagonists; natriuresis Author Affiliation: Bayer Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal (Germany) Bayer Pharma AG, DMPK, 42096 Wuppertal (Germany) Bayer Pharma AG, Chemical Development, 42096 Wuppertal (Germany) Bayer Pharma AG, Cardiology Research, 42096 Wuppertal (Germany) Bayer Pharma AG, Medicinal Chemistry Wuppertal, 42096 Wuppertal (Germany)

Subject(s): BAY 94-8862 ; cardiorenal disease ; Care and treatment ; Heart failure ; MR antagonists ; natriuresis ; Steroids

ISSN: 1860-7179

E-ISSN: 1860-7187

DOI: 10.1002/cmdc.201290035

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5

Article

Improved Synthesis of the Selective Rho-Kinase Inhibitor 6-Chloro-N4-{3,5-difluoro-4-[(3-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]phenyl}pyrimidin-2,4-diamine

Schirok, Hartmut ; Paulsen, Holger ; Kroh, Walter ; [et al.]

2010

ISSN: 1083-6160

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Language: English

In: Organic process research & development, 2010-01-15, Vol.14 (1), p.168-173

Description: A highly potent and selective Rho-kinase inhibitor containing a 7-azaindole moiety has been developed at Bayer Schering Pharma. Herein we disclose details of a significantly improved synthesis of the compound in 8.2% overall yield. Key aspects include cost and safety considerations and the uncommon use of a trifluoromethyl group with controllable reactivity as a masked methyl group.

ISSN: 1083-6160

E-ISSN: 1520-586X

DOI: 10.1021/op900260k

Source: Hellenic Academic Libraries Link

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6

Article

Chromanol derivatives—A novel class of CETP inhibitors

Vakalopoulos, Alexandros ; Schmeck, Carsten ; Thutewohl, Michael ; [et al.]

2011

ISSN: 0960-894X

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Language: English

In: Bioorganic & medicinal chemistry letters, 2011-01-01, Vol.21 (1), p.488-491

Description: A novel chemical class of active cholesteryl ester transfer protein (CETP) inhibitors were prepared and an evaluation of the structure–activity relationships of these chromanols is described. Compound 19b was identified as a potent CETP inhibitor with an excellent in vitro and PK-profile. Based on our former development candidate BAY 38-1315, optimization efforts led to the discovery of a novel chemical class of orally active cholesteryl ester transfer protein (CETP) inhibitors. The chromanol derivative 19b is a highly potent CETP inhibitor with favorable pharmacokinetic properties suitable for clinical studies. Chemical process optimization furnished a robust synthesis for a kilogram-scale process.

Subject(s): Administration, Oral ; Animals ; Benzopyrans - chemical synthesis ; Benzopyrans - chemistry ; Benzopyrans - pharmacokinetics ; Biological and medical sciences ; CETP inhibitor ; Cholesterol Ester Transfer Proteins - antagonists & inhibitors ; Cholesterol Ester Transfer Proteins - metabolism ; Cholesterol, HDL - metabolism ; Chromanols ; Chromans - chemical synthesis ; Chromans - chemistry ; Chromans - pharmacokinetics ; Dogs ; General and cellular metabolism. Vitamins ; HDL ; Humans ; Medical sciences ; Mice ; Mice, Transgenic ; Pharmacology. Drug treatments ; Rats ; Spiro Compounds - chemical synthesis ; Spiro Compounds - chemistry ; Spiro Compounds - pharmacokinetics ; Structure-Activity Relationship ; Torcertrapib

ISSN: 0960-894X

E-ISSN: 1464-3405

DOI: 10.1016/j.bmcl.2010.10.110

Source: Backfile Package - All of Back Files EBS [ALLOFBCKF]

URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23726846$$DView record in Pascal Francis

URL: https://www.ncbi.nlm.nih.gov/pubmed/21084191$$D View this record in MEDLINE/PubMed

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7

Article

Scalable Synthesis of the Desoxy-biphenomycin B Core

Berwe, Mathias ; Jöntgen, Winfried ; Krüger, Jochen ; [et al.]

2011

ISSN: 1083-6160

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Language: English

In: Organic process research & development, 2011-11-18, Vol.15 (6), p.1348-1357

Description: We describe the evolution of a kilogram-scale synthesis of the protected cyclic tripeptide desoxy-biphenomycin B, based on an early discovery route. The retrosynthetic concept included a macrolactamization strategy to build the core ring system of biphenomycin B in combination with a double catalytic asymmetric hydrogenation protocol for the construction of the ansa-tripeptide precursor. Eventually, the kilogram process comprised a 16-step sequence with an overall yield for the longest linear sequence of 19.5%.

ISSN: 1083-6160

E-ISSN: 1520-586X

DOI: 10.1021/op200207h

Source: Hellenic Academic Libraries Link

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8

Article

Efficient Regioselective Synthesis of 6-Amino-5-benzoyl-1-Substituted 2(1H)-Pyridinones

Schirok, Hartmut ; Alonso-Alija, Cristina ; Benet-Buchholz, Jordi ; [et al.]

2005

ISSN: 0022-3263

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Language: English

In: Journal of organic chemistry, 2005-11-11, Vol.70 (23), p.9463-9469

Description: A regioselective and efficient approach toward 6-amino-5-benzoyl-1-substituted 2(1H)-pyridinones by reaction of acyclic ketene aminals with propiolic acid ester was developed. The effect of the solvent and temperature on the regioselectivity of the reaction and the compatibility of the target compounds to functional group manipulations was examined. Substrates with an ortho substituent build atropisomers due to the restricted rotation around the C−N bond. The enantiomers were separated, and the barrier of rotation was determined experimentally. Quantum chemical calculations allowed a ranking of the barrier heights, and a new mechanism of rotation by deformation of the central pyridinone moiety is proposed.

Subject(s): Amino compounds ; Chemical properties ; Chemistry ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with only one n hetero atom and condensed derivatives ; Kinetics and mechanisms ; Models, Chemical ; Molecular Conformation ; Molecular Structure ; Organic chemistry ; Preparations and properties ; Pyridine ; Pyridones - chemical synthesis ; Quantum chemistry ; Reactivity and mechanisms ; Research ; Stereoisomerism

ISSN: 0022-3263

E-ISSN: 1520-6904

DOI: 10.1021/jo0515428

Source: Hellenic Academic Libraries Link

URL: http://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17256498$$DView record in Pascal Francis

URL: https://www.ncbi.nlm.nih.gov/pubmed/16268621$$D View this record in MEDLINE/PubMed

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9

Article

Medicinal Chemistry Optimization of Acyldepsipeptides of the Enopeptin Class Antibiotics

Hinzen, Berthold ; Raddatz, Siegfried ; Paulsen, Holger ; [et al.]

2006

ISSN: 1860-7179

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Language: English

In: ChemMedChem, 2006-07-10, Vol.1 (7), p.689-693

Description: The therapy of life‐threatening infections is significantly weakened by the global spread of antibiotic resistance. Synthetic exploration of enopeptin type acyldepsipeptide antibiotics revealed a remarkable structure–activity relationship. New compounds with improved in vitro antibiotic activity against Gram‐positive pathogens (including multiresistant strains) and in vivo activity in mouse models of lethal infection are described.

Subject(s): Anti-Bacterial Agents - chemical synthesis ; Anti-Bacterial Agents - chemistry ; Anti-Bacterial Agents - pharmacology ; antibiotics ; Bacillus subtilis - drug effects ; Bacillus subtilis - ultrastructure ; Chemistry, Pharmaceutical ; Crystallography, X-Ray ; drug resistance ; Gram-positive bacteria ; Gram-Positive Bacteria - drug effects ; Gram-Positive Bacterial Infections - drug therapy ; Peptides, Cyclic - chemical synthesis ; Peptides, Cyclic - chemistry ; Peptides, Cyclic - pharmacology ; structure-activity relationships

ISSN: 1860-7179

E-ISSN: 1860-7187

DOI: 10.1002/cmdc.200600055

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Source: Wiley-Blackwell Full Collection 2014

URL: https://www.ncbi.nlm.nih.gov/pubmed/16902918$$D View this record in MEDLINE/PubMed

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10

Article

Synthesis and Derivatization of 3-Perfluoroalkyl-Substituted 7-Azaindoles

Schirok, Hartmut ; Figueroa-Pérez, Santiago ; Thutewohl, Michael ; [et al.]

2007

ISSN: 0039-7881

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Language: English

In: Synthesis (Stuttgart), 2007-01-17, Vol.2007 (2), p.251-258

Description: ABSTRACT An expedient large-scale synthesis of 3-perfluoroalkyl-7-azaindoles starting from 2-fluoropyridine is presented. The activation as 6-chloro-4-nitro derivative allows the further derivatization by nucleophilic aromatic substitution in the 4-position.

Subject(s): paper

ISSN: 0039-7881

E-ISSN: 1437-210X

DOI: 10.1055/s-2006-958935

Source: Thieme Zeitschriftenarchive (DFG Nationallizenzen)

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