Activation of androgen receptor (AR) is crucial for prostate cancer growth. Remarkably, also castration-resistant prostate cancer (CRPC) is dependent on functional AR, and several mechanisms have been proposed to explain the addiction. Known causes of CRPC include gene amplification and overexpression as well as point mutations of AR. We report here the pharmacological profile of ODM-201, a novel AR inhibitor that showed significant antitumor activity and a favorable safety profile in phase 1/2 studies in men with CRPC. ODM-201 is a full and high-affinity AR antagonist that, similar to second-generation antiandrogens enzalutamide and ARN-509, inhibits testosterone-induced nuclear translocation of AR. Importantly, ODM-201 also blocks the activity of the tested mutant ARs arising in response to antiandrogen therapies, including the F876L mutation that confers resistance to enzalutamide and ARN-509. In addition, ODM-201 reduces the growth of AR-overexpressing VCaP prostate cancer cells both in vitro and in a castration-resistant VCaP xenograft model. In contrast to other antiandrogens, ODM-201 shows negligible brain penetrance and does not increase serum testosterone levels in mice. In conclusion, ODM-201 is a potent AR inhibitor that overcomes resistance to AR-targeted therapies by antagonizing both overexpressed and mutated ARs. ODM-201 is currently in a phase 3 trial in CRPC.

The aldol-Tishchenko reaction of enolizable aldehydes is a simple and effective way to prepare 1,3-diol monoesters, which are widely used as coalescing agents in the paint industry. The use of monoalcoholates of 1,3-diols as catalysts gives fast and clean reactions compared with the previous use of several inorganic catalysts. The use of the proper 1,3-diol moiety in the catalyst also reduces the amount of side products which are due to ester interchange between product esters and the catalyst. The rapid water-free method developed herein allows fast preparation of monoesters with excellent yield and minimized formation of side products.

Shapiro reaction was utilized in an ef®cient route to a Taxole A-ring building block. Commercially available 2-methyl-1,3cyclohexanedione was converted in three simple steps to various arenesulfonylhydrazones and then to the target molecule with the Shapiro reaction. Remarkable differences were observed in the reactivity and stability of different hydrazones and their dianions in the Shapiro reaction. This pathway is the shortest one reported to give the target molecule in good overall yield. The use of different electrophiles in the ®nal Shapiro reaction step allows alternative ways to prepare the target alcohol.

Monoesters of 1,3-diols can be prepared with the mixed Tishchenko reaction from -hydroxy aldehydes and another aldehyde. These two aldehydes form a diastereomeric mixture of 1,3-dioxan-4-ol hemiacetal derivatives which can be further converted to monoesters with suitable catalysts. Limitations in the formation and esterification of this hemiacetal intermediate have been investigated in this work and the formation and stability of 1,3-dioxan-4-ols was found to be aldehyde-, temperature-, and solvent-dependent. A new method was developed for selective preparation of monoesters of 1,3-diols with this mixed Tishchenko reaction via 1,3-dioxan-4-ols without any significant side products. During the development of this method a possibility to scale up the reactions to reach a selective and economical process was one of the main targets in this work.

No abstract