OECD workshop consensus report: Ethical considerations with respect to human derived products, specifically human serum, in OECD test guidelines.

The ethical needs and concerns with use and sourcing of human materials, particularly serum, in OECD test guidelines were explored in a dedicated international workshop held in 2019. The health-related aspects of the donation procedure, including tissue screening, donor health, laboratory work health protection, permission from the donor for commercial use, payment of the donors and the potential for exploitation of low-income populations and data protection of the donors; supply, availability, and competition with clinical needs; traceability of the serum and auditability/GLP needs for the Test Guideline Programme, were examined. Here we provide the recommendations of the workshop with respect to the use of human serum, and potentially other human reagents, specifically with regard to test method development for OECD Test Guideline utility as part of the Mutual Acceptance of Data requirement across all OECD member countries.

On the mechanism of ylide-mediated cyclopropanations: evidence for a proton-transfer step and its effect on stereoselectivity.

In this paper, we describe studies on the cyclopropanation of Michael acceptors with chiral sulfur ylides. It had previously been found that semi-stabilized sulfonium ylides (e.g.

Design of a potent, soluble glucokinase activator with excellent in vivo efficacy.

The optimisation of a series of glucokinase activators is described, including attempts to uncouple the relationship between potency and plasma protein binding, and to better understand the key pharmacokinetic properties of the series. The use of unbound clearance as an optimisation parameter facilitated the identification of GKA50, a compound which combines excellent potency and pharmacokinetics with good free drug levels and solubility, and exhibits in vivo efficacy at 1mg/kg po in an acute rat OGTT model.

Asymmetric sulfonium ylide mediated cyclopropanation: stereocontrolled synthesis of (+)-LY354740.

The reaction of ester-stabilized sulfonium ylides with cyclopentenone to give (+)-5 ((1S,5R,6S)-ethyl 2-oxobicyclo[3.1.0]hexane-6-carboxylate), an important precursor to the pharmacologically important compound (+)-LY354740, has been studied using chiral sulfides operating in both catalytic (sulfide, Cu(acac)2, ethyl diazoacetate, 60 degrees C) and stoichiometric modes (sulfonium salt, base, room temperature).

Discovery, synthesis and biological evaluation of novel glucokinase activators.

The identification, synthesis and SAR of a novel series of glucokinase activators is described. The interplay between lipophilicity, potency and physical properties is discussed, and compound 22 highlighted as having a suitable balance. In vivo pharmacokinetic and acute efficacy studies on this compound are also presented.