Taros Chemicals GmbH and Co. KG

Dortmund, Germany

Taros Chemicals GmbH and Co. KG

Dortmund, Germany
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Giordanetto F.,Astrazeneca | Giordanetto F.,Taros Chemicals Gmbh and Co. KG. | Revell J.D.,MedImmune Ltd | Knerr L.,Astrazeneca | And 5 more authors.
ACS Medicinal Chemistry Letters | Year: 2013

Agonists of vasoactive intestinal peptide receptor 2 (VPAC2) stimulate glucose-dependent insulin secretion, making them attractive candidates for the treatment of hyperglycaemia and type-II diabetes. Vasoactive intestinal peptide (VIP) is an endogenous peptide hormone that potently agonizes VPAC 2. However, VIP has a short serum half-life and poor pharmacokinetics in vivo and is susceptible to proteolytic degradation, making its development as a therapeutic agent challenging. Here, we investigated two peptide cyclization strategies, lactamisation and olefin-metathesis stapling, and their effects on VPAC2 agonism, peptide secondary structure, protease stability, and cell membrane permeability. VIP analogues showing significantly enhanced VPAC2 agonist potency, glucose-dependent insulin secretion activity, and increased helical content were discovered; however, neither cyclization strategy appeared to effect proteolytic stability or cell permeability of the resulting peptides. © 2013 American Chemical Society.

Karawajczyk A.,Taros Chemicals GmbH and Co. KG | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Benningshof J.,Mercachem | Hamza D.,Sygnature Discovery | And 7 more authors.
Drug Discovery Today | Year: 2015

High-throughput screening (HTS) represents a major cornerstone of drug discovery. The availability of an innovative, relevant and high-quality compound collection to be screened often dictates the final fate of a drug discovery campaign. Given that the chemical space to be sampled in research programs is practically infinite and sparsely populated, significant efforts and resources need to be invested in the generation and maintenance of a competitive compound collection. The European Lead Factory (ELF) project is addressing this challenge by leveraging the diverse experience and know-how of academic groups and small and medium enterprises (SMEs) engaged in synthetic and/or medicinal chemistry. Here, we describe the novelty, diversity, structural complexity, physicochemical characteristics and overall attractiveness of this first batch of ELF compounds for HTS purposes.

Over B.,Astrazeneca | McCarren P.,Cambridge Broad Institute | Artursson P.,Uppsala University | Foley M.,Cambridge Broad Institute | And 13 more authors.
Journal of Medicinal Chemistry | Year: 2014

Profiling of eight stereoisomeric T. cruzi growth inhibitors revealed vastly different in vitro properties such as solubility, lipophilicity, pK a, and cell permeability for two sets of four stereoisomers. Using computational chemistry and NMR spectroscopy, we identified the formation of an intramolecular NH-NR3 hydrogen bond in the set of stereoisomers displaying lower solubility, higher lipophilicity, and higher cell permeability. The intramolecular hydrogen bond resulted in a significant pKa difference that accounts for the other structure-property relationships. Application of this knowledge could be of particular value to maintain the delicate balance of size, solubility, and lipophilicity required for cell penetration and oral administration for chemical probes or therapeutics with properties at, or beyond, Lipinski's rule of 5. © 2014 American Chemical Society.

Xiao B.,UK National Institute for Medical Research | Sanders M.J.,UK National Institute for Medical Research | Carmena D.,Imperial College London | Bright N.J.,Imperial College London | And 12 more authors.
Nature Communications | Year: 2013

AMP-activated protein kinase (AMPK) plays a major role in regulating cellular energy balance by sensing and responding to increases in AMP/ADP concentration relative to ATP. Binding of AMP causes allosteric activation of the enzyme and binding of either AMP or ADP promotes and maintains the phosphorylation of threonine 172 within the activation loop of the kinase. AMPK has attracted widespread interest as a potential therapeutic target for metabolic diseases including type 2 diabetes and, more recently, cancer. A number of direct AMPK activators have been reported as having beneficial effects in treating metabolic diseases, but there has been no structural basis for activator binding to AMPK. Here we present the crystal structure of human AMPK in complex with a small molecule activator that binds at a site between the kinase domain and the carbohydrate-binding module, stabilising the interaction between these two components. The nature of the activator-binding pocket suggests the involvement of an additional, as yet unidentified, metabolite in the physiological regulation of AMPK. Importantly, the structure offers new opportunities for the design of small molecule activators of AMPK for treatment of metabolic disorders. © 2013 Macmillan Publishers Limited.

Stotani S.,Taros Chemicals GmbH and Co. KG | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Giordanetto F.,DE Shaw Research | Medda F.,Taros Chemicals GmbH and Co. KG
Future Medicinal Chemistry | Year: 2016

In total, 47,500,000 people worldwide are affected by dementia and this number is estimated to double by 2030 and triple within 2050 resulting in a huge burden on public health. Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia, accounting for 60-70% of all the cases. The cause of AD is still poorly understood but several brain abnormalities (e.g., loss of neuronal connections and neuronal death) have been identified in affected patients. In addition to the accumulation of β-amyloid plaques in the brain tissue, aberrant phosphorylation of tau proteins has proved to increase neuronal death. DYRK1A phosphorylates tau on 11 different Ser/Thr residues, resulting in the formation of aggregates called 'neurofibrillary tangles' which, together with amyloid plaques, could be responsible for dementia, neuronal degeneration and cell death. Small molecule inhibition of DYRK1A could thus represent an interesting approach toward the treatment of Alzheimer's and other neurodegenerative diseases. Herein we review the current progress in the identification and development of DYRK1A inhibitors. © 2016 Future Science Ltd.

Murali A.,Max Planck Institute For Molekulare Physiologie | Medda F.,Taros Chemicals GmbH and Co. KG | Winkler M.,Taros Chemicals GmbH and Co. KG | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Kumar K.,Max Planck Institute For Molekulare Physiologie
Bioorganic and Medicinal Chemistry | Year: 2015

An efficient synthetic access to two amino-oxazoline compound libraries was developed employing the branching cascades approach. A common precursor, that is, chromonylidene β-ketoester was transformed into two different ring-systems, that is, the pyridine and the benzopyrane substituted hydroxyphenones. In further two steps, the ketone moiety in two ring-systems was transformed into an amino-oxazoline ring. The functional groups on the two amino-oxazoline scaffolds were exploited further to generate, a compound collection of ca. 600 amino-oxazolines which are being exposed to various biological screenings within the European Lead Factory consortium. © 2015 The Authors.

Giordanetto F.,Astrazeneca | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Kihlberg J.,Astrazeneca | Kihlberg J.,Uppsala University
Journal of Medicinal Chemistry | Year: 2014

Macrocycles are ideal in efforts to tackle "difficult" targets, but our understanding of what makes them cell permeable and orally bioavailable is limited. Analysis of approximately 100 macrocyclic drugs and clinical candidates revealed that macrocycles are predominantly used for infectious disease and in oncology and that most belong to the macrolide or cyclic peptide class. A significant number (N = 34) of these macrocycles are administered orally, revealing that oral bioavailability can be obtained at molecular weights up to and above 1 kDa and polar surface areas ranging toward 250 Å2. Moreover, insight from a group of "de novo designed" oral macrocycles in clinical studies and understanding of how cyclosporin A and model cyclic hexapeptides cross cell membranes may unlock wider opportunities in drug discovery. However, the number of oral macrocycles is still low and it remains to be seen if they are outliers or if macrocycles will open up novel oral druggable space. © 2013 American Chemical Society.

Picazo E.,Taros Chemicals GmbH and Co. KG | Giordanetto F.,Taros Chemicals GmbH and Co. KG
Drug Discovery Today | Year: 2015

Ebola viruses are extremely virulent and highly transmissible. They are responsible for sporadic outbreaks of severe hemorrhagic fevers with human mortality rates of up to 90%. No prophylactic or therapeutic treatments in the form of vaccine, biologicals or small molecule, currently exist. Yet, a wealth of antiviral research on ebola virus is being generated and potential inhibitors have been identified in biological screening and medicinal chemistry programs. Here, we detail the state-of-the-art in small molecule inhibitors of ebola virus infection, with >60 examples, including approved drugs, compounds currently in clinical trials, and more exploratory leads, and summarize the associated in vitro and in vivo evidence for their effectiveness. © 2014 Elsevier Ltd.

Doak B.C.,Uppsala University | Over B.,Astrazeneca | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Kihlberg J.,Uppsala University
Chemistry and Biology | Year: 2014

The rule of 5 (Ro5) is a set of in silico guidelines applied to drug discovery to prioritize compounds with an increased likelihood of high oral absorption. It has been influential in reducing attrition due to poor pharmacokinetics over the last 15 years. However, strict reliance on the Ro5 may have resulted in lost opportunities, particularly for difficult targets. To identify opportunities for oral drug discovery beyond the Ro5 (bRo5), we have comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da. We conclude that oral drugs are found far bRo5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability. Natural products and structure-based design, often from peptidic leads, are key sources for oral bRo5 drugs. These insights should help guide the design of oral drugs in bRo5 space, which is of particular interest for difficult targets. ©2014 Elsevier Ltd All rights reserved.

Giordanetto F.,Astrazeneca | Giordanetto F.,Taros Chemicals GmbH and Co. KG | Barlaam B.,Astrazeneca | Berglund S.,Astrazeneca | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

Optimization of AZD6482 (2), the first antiplatelet PI3Kβ inhibitor evaluated in man, focused on improving the pharmacokinetic profile to a level compatible with once daily oral dosing as well as achieving adequate selectivity towards PI3Kα to minimize the risk for insulin resistance. Structure-based design and optimization of DMPK properties resulted in (R)-16, a novel, orally bioavailable PI3Kβ inhibitor with potent in vivo anti-thrombotic effect with excellent separation to bleeding risk and insulin resistance. © 2014 Elsevier Ltd. All rights reserved.

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