Science Pool

Selective P2X3 Receptor Antagonist, Eliapixant, for Treatment of Hypersensitive Nerve Fibre Disorders

Posted by Evotec on Oct 7, 2021 11:56:52 AM

P2X3 receptors play an important role in the sensitisation of nerve fibres and pain pathways. Involvement in pathways triggering cough and contribution to the pathophysiology of endometriosis and overactive bladder have also been reported. Development of P2X antagonists have been hampered by off‑target effects which include severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer.  

In this publication, we focus on:

  • how eliapixant (BAY 1817080), a P2X3 receptor antagonist, is both highly potent and selective for P2X3 over other P2X subtypes in vitro including P2X2/3
  • how eliapixant reduces inflammatory pain in relevant animal models
  • experimental evidence that P2X3 antagonism reduces neurogenic inflammation and vaginal pain, and demonstration of the potential use of eliapixant in endometriosis

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Tags: Neuroscience, Articles & Whitepapers, In vitro Biology, In vivo Pharmacology

Discovery of Novel UDP-N-Acetylglucosamine Acyltransferase (LpxA) Inhibitors

Posted by Evotec on Sep 30, 2021 7:41:42 PM

Alastair Parkes, Ph.D, Group Leader, Discovery Chemistry, Evotec UK

As part of our ongoing efforts at Evotec to tackle AMR through the design of novel antibiotics we have been working with Boston-based X-Biotix in a collaboration focussed on targeting priority Gram-negative pathogens. We are now able to share the story of our work on inhibitors of UDP-N-Acetylglucosamine Acyltransferase (LpxA), a key enzyme in the biosynthetic pathway of the outer membrane lipopolysaccharide of Gram-negative bacteria. Building on hit-finding work at X-Biotix we put together a multi-disciplinary team including Medicinal Chemistry, Computational Chemistry, Structural Biology and DMPK at our Abingdon UK site, in vitro and in vivo Microbiology and PK at our Alderley Park UK site, and in vitro Biology at our site in Hamburg, Germany. Through structure and property-based optimisation we were able to design highly potent inhibitors of Pseudomonas aeruginosa LpxA that were active against multi-drug resistant clinical isolates. To our knowledge, this is the first reported LpxA inhibitor series with selective activity against P. aeruginosa bacteria. In our paper in the Journal of Medicinal Chemistry we share the optimisation story, along with a significant quantity of activity data that we hope will be useful for other teams working on small molecule strategies to tackle P. aeruginosa and other Gram-negative bacteria.

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Tags: Antibacterial, Medicinal Chemistry, Articles & Whitepapers, ADME/DMPK, In vitro Biology, In vivo Pharmacology, Anti-Infectives, Antimicrobial resistance

PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates

Posted by Evotec on Sep 13, 2021 8:09:42 PM

Mutant huntingtin (mHTT) protein has been implicated in neuronal degeneration in Huntington's Disease.

In this publication, we focus on:

  • a background to the inherited neurodegenerative disorder, Huntington's Disease, including the impact of the mutant huntingtin (mHTT) gene
  • a discussion of the use of positron emission tomography (PET) to monitor disease progression
  • the identification of a novel ligand CHDI-626 which binds to mHTT aggregates

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Tags: Neuroscience, Articles & Whitepapers, In vitro Biology, In vivo Pharmacology

Development of Potential PET Ligand for Imaging Mutant Huntingtin Aggregates

Posted by Evotec on Sep 13, 2021 8:06:10 PM

Mutant huntingtin (mHTT) forms protein aggregates characteristic of Huntington's Disease pathology.

In this publication, we focus on:

  • a background to Huntington's Disease including the mutant huntingtin gene (mHTT)
  • a discussion of the benefits of sensitive biomarkers to monitor disease progression
  • the discovery of an mHTT aggregate-specific PET ligand suitable for live brain imaging

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Tags: Neuroscience, Articles & Whitepapers, In vivo Pharmacology

Pharmacological Characterization of Mutant Huntingtin Aggregate-Directed PET Imaging Tracer Candidates

Posted by Evotec on Sep 13, 2021 8:03:47 PM

Huntington's Disease is caused a mutation in the huntingtin (mHTT) gene which codes for the huntingtin (HTT) protein.

In this publication, we focus on:

  • a background to link between Huntington's Disease and the mutant huntingtin gene (mHTT)
  • the development of PET tracers for imaging mHTT aggregates
  • characterisation of these PET tracers including pharmacological investigation of their binding affinities and selectivity

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Tags: Neuroscience, Articles & Whitepapers, In vitro Biology, In vivo Pharmacology

Potent and Selective Agonists of Human TRPM5

Posted by Evotec on Jun 17, 2021 5:49:12 PM

Tags: Articles & Whitepapers, Hit & Target ID/Validation, In vivo Pharmacology

Hydroxyproline Quantitation in Bleomycin-induced Lung Fibrosis Model

Posted by Evotec on Apr 22, 2021 9:22:39 AM


Tags: Respiratory, Posters, In vivo Pharmacology

Inhibition of NF-kB Inducing Kinase in IFNα-accelerated Lupus Nephritis

Posted by Evotec on Mar 5, 2021 5:36:55 PM

Tags: Kidney diseases, Articles & Whitepapers, In vivo Pharmacology, Immunology & Inflammation, Metabolic Disease & Complications

Design of Clinical Trials in Patients with Decompensated Cirrhosis

Posted by Evotec on Mar 4, 2021 10:53:37 PM

Tags: Articles & Whitepapers, In vivo Pharmacology

ABHD11: A New Diacylglycerol Lipase Involved in Weight Gain Regulation

Posted by Evotec on Mar 4, 2021 10:52:37 PM

Tags: Articles & Whitepapers, In vivo Pharmacology, Metabolic Disease & Complications