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Nottingham, United Kingdom

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.

Storr T.E.,University of Nottingham | Cully S.J.,University of Nottingham | Rawling M.J.,University of Nottingham | Lewis W.,University of Nottingham | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

The application of a tandem condensation/cyclisation/[3+2]-cycloaddition/elimination reaction gives an sp3-rich tricyclic pyrazoline scaffold with two ethyl esters in a single step from a simple linear starting material. The successive hydrolysis and cyclisation (with Boc anhydride) of these 3-dimensional architectures, generates unprecedented 16-membered macrocyclic bisanhydrides (characterised by XRD). Selective amidations could then be achieved by ring opening with a primary amine followed by HATU-promoted amide coupling to yield an sp3-rich natural product-like library. © 2015 Elsevier B.V. All rights reserved.

Farinha C.M.,University of Lisbon | King-Underwood J.,Sygnature Discovery | Sousa M.,University of Lisbon | Correia A.R.,New University of Lisbon | And 7 more authors.
Chemistry and Biology | Year: 2013

Cystic fibrosis is mostly caused by the F508del mutation, which impairs CFTR protein from exiting the endoplasmic reticulum due to misfolding. VX-809 is a small molecule that rescues F508del-CFTR localization, which recently went into clinical trial but with unknown mechanism of action (MoA). Herein, we assessed if VX-809 is additive or synergistic with genetic revertants of F508del-CFTR, other correctors, and low temperature to determine its MoA. We explored and integrated those various agents in combined treatments, showing how they add to each other to identify their complementary MoA upon correction of F508del-CFTR. Our experimental and modeling data, while compatible with putative binding of VX-809 to NBD1:ICL4 interface, also indicate scope for further synergistic F508del-CFTR correction by other compounds at distinct conformational sites/cellular checkpoints, thus suggesting requirement of combined therapies to fully rescue F508del-CFTR. © 2013 Elsevier Ltd.

Nickel S.,Universtitat Duisburg Essen | Nickel P.,Universtitat Duisburg Essen | Hellmert M.,Universtitat Duisburg Essen | Ernst S.,Universtitat Duisburg Essen | And 5 more authors.
Bioorganic and Medicinal Chemistry | Year: 2015

Scaffolds of natural products represent promising starting points for the development of focused compound libraries. Here, we describe the development of a synthetic route to a compound library based on the hexahydropyrrolo indole (HPI) scaffold, the denoting structural motif of the HPI natural product family. To this end, a two-step approach consisting of a batch synthesis of an advanced functionalizable HPI intermediate followed by the establishment of reaction conditions that allow derivatization of this scaffold at three different positions is described. Subsequently, the optimized methods were applied to the synthesis of a 276-member library. © 2015 Elsevier Ltd. All rights reserved.

Hunt H.J.,Corcept Therapeutics | Belanoff J.K.,Corcept Therapeutics | Golding E.,Sygnature Discovery | Gourdet B.,Sygnature Discovery | And 5 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2015

We report the further optimization of our series 1H-pyrazolo[3,4-g]hexahydro-isoquinoline sulfonamides as GR antagonists. By incorporating a heteroaryl ketone group at the ring junction, we have obtained compounds with excellent functional GR antagonism. Optimization of the sulfonamide substituent has provided compounds with a very desirable overall profile, including minimal hERG activity, good bioavailability and in vivo efficacy. © 2015 Elsevier Ltd.

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