Metabolic Clearance Data
The MetaSite metabolism prediction tool was used to evaluate potential metabolic hotspots.
Thiophenes in particular are prone to CYP-mediated oxidation and the creation of metabolites that may react with nucleophiles present in biological systems. In addition to accelerating clearance, the products of these reactions are potentially toxic at high doses (reference). One of the major goals of this project is to address the metabolic liabilities of this compound. Based on known oxidation patterns of thiophenes, we have proposed the following structures as likely metabolites of OSA_000822:
The first round of clearance data from Monash U. is summarized in the table below. Prior to OSA work on the series, SB-400868 and two focused array compounds were evaluated in MLM and RLM at UNC (original reports found here). In the first round, these compounds and two additional ones were evaluated in HLM and RLM at Monash University (discussion here and full report here).
ADME data on a second round of compounds. Discussion at Issue #104
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A subset of compounds were evaluated against a full ADME panel (LogD, aq. solubility, HLM Clint, rat hep. Clint, and PPB. Discussion of the results may be found at Issue #80, #81, and #82.
The compounds donated by DNDi/NEU have been evaluated for aqueous solubility, PPB, clearance, and LogD.
Currently, there is funding available for:
- In vitro microsomal clearance assays and kinetic solubility assays for 9 compounds. (As of Sept 2020, five of these slots have been used.)
- In vivo PK studies measuring %F, half-life, Vd, and clearance for 1 compound with iv and po administration.
These assays will be performed at Monash University.
Note that there was a discussion about standard units here. The units apparently differ between Monash and UNC, but the numbers are saying equivalent things, since the units denote a slightly different meaning (in vitro vs extrapolated in vivo experiment).
OSA_000821 was screened by Hypha against their PolyCYP and AOX/FMO3 panel, with the major metabolite isolated and characterised. The metabolite was identified to be hydroxylated on the southern-most methylene carbon (characterisation data here and here). This result is in line with the predicted metabolic hotspot for the analogous compound OSA_000822 above.
