Novel CB1 Inhibitors from the Fungus UK-143

Obesity has been one of the most serious challenges for public health and is purported to cause over 100,000 deaths every year in the United States alone. Moreover, obesity has increased worldwide by 75% since 1980, and consequently it has been defined as a global epidemic by WHO. Therefore, there is an urgent medical need to develop the effective and safe treatment of obesity [1]. The discovery of the endocannabinoid system provides a promising target for obesity therapy and intense research efforts in the past two decades have led to the discovery of several CB1 antagonists including rimonabant and taranabant. Recently they were not approved for the treatment of obesity because of severe psychiatric side effects [2]. Whether side effect of these compounds results from the mechanism of action themselves or if these are specific and selective compounds remains a mystery. It is therefore important and urgent to identify and develop novel and selective CB1 antagonists that may exhibit a distinct and attractive therapeutic profile. One fungal species UK-143 was found to exhibit >50% inhibition at 100 nM in a CB1 competitive binding assay and was further followed by bioassay-guided isolation. The most potent compound has a CB1 Ki of 22 nM and >10-fold selectivity against the CB2 receptor. References: [1] Bray GA (2006) Journal of Medicinal Chemistry 49: 4001–4007. [2] Wu CH, Huang MS, et al. (2009) Journal of Medicinal Chemistry 52: 4496–4510.