Agora 3

Description:
mitochondrial modulators with benzothiazolylurea core structure

Mode of action:
amyloid-binding alcoholdehydrogenase (ABAD) inhibition

Licensed:
University of Hradec Kralove, Czech Republic
University Hospital Hradec Kralove, Czech Republic
University of St. Andrews, Scotland, Great Britain
Czech patent No. 305 633

It is generally known that amyloid beta peptide plays a crucial role in pathogenesis and progression of Alzheimer’s disease. Recently, it has been revealed that Aβ interacts with mitochondrial enzyme – amyloid-β binding alcohol dehydrogenase (ABAD). ABAD is a 27 kDa multifunctional enzyme localized in mitochondrial matrix, where it catalyzes reduction of aldehydes and ketones as well as alcohol oxidation. Furthermore, the in vitro results have disclosed that interaction between ABAD and Aβ is cytotoxic causing mitochondrial dysfunction, increased reactive oxygen species production and subsequently cell death. Therefore, direct ABAD inhibition may represent a novel strategy in Alzheimer’s disease therapy. In 2006 Xie et al. described frentizol – a novel compound able to inhibit ABAD-Aβ interaction (Fig. 1). Frentizol is a weak inhibitor with IC50 value of approx. 200 μM. The objective of this patent are novel ABAD inhibitors with benzothiazolylurea core structure.

Chemical structures of frentizol and K690

Figure 1. Chemical structures of frentizol and K690

As the most promising candidate of the series was highlighted derivate K690 (Fig. 1). It’s IC50 value towards ABAD enzyme was 2.00 μM, which is comparing to the standard – frentizol – 100-fold more potent. Furthermore, K690 proved inhibitory activities towards other mitochondrial enzymes, e.g. Complex I of mitochondrial respiration, MAO-A, MAO-B etc. Obtained results are illustrated in Table 1. Finally, it should be mentioned, that at the concentration 200 mg/kg it exerted no toxic effect in mice, making this class of drugs very auspicious in the way of searching for novel alternative treatments of AD.


Table 1. Results of in vitro screening of K690

Compound human ABAD inhibition
IC50 (µM)
pig Complex I-linked mitochondrial respiration inhibition
IC50 (µM)
pig Complex II-linked respiration inhibition
IC50 (µM)
pig MAO-A inhibition
IC50 (µM)
pig MAO-B inhibition
IC50 (µM)
MTT cell viability (CHO-K1 cell line)
IC50 (µM)
K690 2.00 15.95 141.3 25.8 95 17


Discovery Lead-ident. Lead-optim. Preclinics Phase 1 Phase 2 Phase 3
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