Discovery and development of ODM-204: A Novel nonsteroidal compound for the treatment of castration-resistant prostate cancer by blocking the androgen receptor and inhibiting CYP17A1.

We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropin-treated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.

Garner's aldehyde as a versatile intermediate in the synthesis of enantiopure natural products.

Since its introduction to the synthetic community in 1984, Garner's aldehyde has gained substantial attention as a chiral intermediate for the synthesis of numerous amino alcohol derivatives. This review presents some of the most successful carbon chain elongation reactions, namely carbonyl alkylations and olefinations. The literature is reviewed with particular attention on understanding how to avoid the deleterious epimerization of the existing stereocenter in Garner's aldehyde.

Asymmetric synthesis of Pachastrissamine (Jaspine B) and its diastereomers via η3-allylpalladium intermediates.

A short route for the synthesis of Pachastrissamine (Jaspine B), an anhydrosphingosine derivative, and all three of its diastereomers is presented. The route consists of only 9 steps from the commercially available Garner's aldehyde. The furan framework is formed via an η(3)-allylpalladium intermediate.

Short and straightforward synthesis of (-)-1-deoxygalactonojirimycin.

The mildness and low basicity of vinylzinc species functioning as a nucleophile in addition to alpha-chiral aldehydes is characterized by lack of epimerization of the vulnerable stereogenic center. This is demonstrated by a highly diastereoselective synthesis of 1-deoxygalactonojirimycin in eight steps from commercial starting materials with overall yield of 35%.