News

We are pleased that a paper by Salter et al., 2018 has been published in Xenobiotica. The paper, entitled Microbial Biotransformation – An Important Tool for the Study of Drug Metabolism, describes some interesting projects Hypha have undertaken for Merck and Janssen with several difficult-to-synthesize hydroxylated and glucuronidated metabolites.

A 2018 Nature Reviews Drug Discovery paper by Bostrom et al on “Expanding the medicinal chemistry synthetic toolbox” features examples of the outputs of Hypha’s hydroxylation technology. Hydroxylation is a key tactic to consider as part of a late stage functionalization strategy where small changes can result in improved activity, selectivity, solubility and lipophilicity.

Zhou et al.  presented a poster at the 2018 ISSX Conference in Montreal on “Elimination of [14C]-LY3023414 by Aldehyde Oxidase and CYP Enzymes in Humans Following Oral Administration.”  Both AO and CYP enzymes were responsible for the metabolic clearance of LY3023414 with the non-CYP enzymes mediating approximately half of the clearance of the drug. Hypha Discovery made three of the metabolites used in this study undertaken by Lilly.

Hypha Discovery have issued a policy detailing our position on data protection in relation to the GDPR regulations that came into force at the end of May 2018. You can read this policy via the link below.

Many drugs and chemicals possess complex metabolism including those metabolized through both oxidative and conjugative routes. Our newsletter highlights two case studies where sequential oxidation and glucuronidation resulted in major human and mammalian metabolites that were required in mg-g scale for further testing. Read more in our newsletter here.

Hypha’s newsletter for Q4 2017 focusses on the selective production of N-oxide metabolites, especially relevant where there is potential for N-oxidation at multiple positions in the parent drug. We also discuss instability of some N-oxide metabolites and the impact of reversion back to the parent.

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.