News

This quarter we look at interesting off-target activity of some drug metabolites, using the metabolism of valsartan to 4-hydroxyvaleryl-valsartan as a case study.

Scientists in the AgChem industry often need to access metabolites of pesticides and herbicides to meet regulatory requirements. For more information on how Hypha’s biocatalysis approach can help fulfil these requirements, click here for a case study in which glucuronidated metabolites of the herbicide napropamide were produced and structures confirmed by NMR spectroscopy.

This issue of Hypha’s newsletter focusses on accessing the major circulating and excretory metabolites of the drug lorcaserin. In particular we look at scalable mechanisms for obtaining N-carbamoyl glucuronides and N-sulfamate metabolites of drugs containing primary or secondary amino functionalities using lorcaserin as a case study.

Ingenol disoxate is a chemically-stable drug developed by LEO Pharma, effective at treating actinic keratosis topically and currently in Phase 3 clinical trials. Profiling of ingenol disoxate against multiple species of hepatocytes, revealed M27 as a predominant metabolite, particularly in human hepatocytes. Although accurate mass spectrometry indicated the metabolite was mono-hydroxylated in the ingenol moiety, the precise location of the hydroxyl group could not be identified. Consequently, chemical synthesis was not feasible, nor biological quantification and further biological testing possible.

Hypha’s newsletter for Q2 focusses on aspects of the metabolism of the experimental anti-cancer drug tivantinib. Tivantinib is extensively metabolised in humans including to various hydroxylated metabolites, of which two are major metabolites implicated under the FDA MIST guideline. Read more about how these human metabolites and other derivatives can be produced via microbial biocatalysis by clicking on the link below.

This quarter we illustrate a case study describing the successful provision of hundreds of milligrams of a major hydroxylated metabolite to a client for unambiguous structure determination and, critically, for biological tests requested by the FDA. The topical dermal drug is currently in Phase 3 clinical trials and access to scalable amounts of the metabolite was important in satisfying aspects of safety testing for MIST compliance.

Our new brochure on drug metabolites and C-H activated derivatives is now available. Inside we feature interesting case studies and client projects, including the following topics:

Our newsletter for Q4 2016 features case studies illustrating the creation of sulfated metabolites and, in some cases, co-production of other conjugates.

Hot-off-the-press news describing the scale-up of human metabolites resulting from mixed metabolism of Incyte’s first-in-class IDO1 inhibitor epacadostat (EPA) is the topic of our newsletter for Q3. EPA is currently in Phase III clinical trials in combination with Merck’s pembrolizumab for treatment of metastatic melanoma.

Scientists at Lilly presented a poster at ISSX 2015 summarising results of an evaluation of Hypha’s drug metabolite screening panels. In it they conclude:

Dr Steve Wrigley will be talking at the forthcoming RSC conference “Bioactive Natural Products: Translating Promise into Practice” to be held at St. Catherine’s College, University of Oxford, UK on 11-13 July 2016.

Steve’s talk is entitled, “Diversity and Diversification : Microbial Chemistry for Discovery and Development.”

Hypha will showcase its expertise in DMPK metabolite synthesis at the 3rd New Perspectives in DMPK: the impact of drug design, 8th-9th February 2016 at the Royal Society of Chemistry at Burlington House, London. Hypha are experts in producing up to gram amounts of metabolites that are hard to make synthetically. Hypha’s microbial system mimics mammalian metabolism with a very high success rate and performs difficult reactions including aliphatic hydroxylations and glucuronidations.