Abstract
YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation.
Highlights
Pirinixic acid [1, Wy-14643, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid; Figure 1] was discovered in the 1970s, during the development of new agents against hypercholesterolemia [1]
YS-121 was synthesized in a four-step reaction originally published by d’Atri et al [10] and already modified by Koeberle et al [8]
Through a nucleophilic aromatic substitution at the pyrimidine core of 5, one chloro group was substituted by 2,3-dimethylaniline with triethylamine in EtOH to form the monoaminated derivative ethyl 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoate (6, iii a)
Summary
Pirinixic acid [1, Wy-14643, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid; Figure 1] was discovered in the 1970s, during the development of new agents against hypercholesterolemia [1]. In 1977, it was identified to be a peroxisome proliferator [2]. After the discovery of the peroxisome proliferator-activated receptor (PPAR) in 1990 [3], the agonistic activity of pirinixic acid at PPARα and PPARγ was detected within the ten years [4,5]. YS-121 [2, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid; Figure 2] is the result of target-oriented structural derivatization of pirinixic acid [6]. That structural modification enhanced PPARα and PPARγ agonism to values in the low micromolar range [EC50 = 1.0 μM (α) and 3.6 μM (γ) in a cell-based luciferase reporter gene assay] [6].
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