The androgens testosterone (T) and dihydrotestosterone (DHT), besides playing an important role in prostate development and growth, are also responsible for the development and progression of benign prostate hyperplasia (BPH) and prostate cancer. Therefore, the actions of these hormones can be antagonized by preventing the irreversible conversion of T into DHT by inhibiting 5a-reductase (5a-R). This has been a useful therapeutic approach for the referred diseases and can be achieved by using 5areductase inhibitors (RIs). Steroidal RIs, finasteride and dutasteride, are used in clinic for BPH treatment and were also proposed for chemoprevention of prostate cancer. Nevertheless, due to the increase in bone and muscle loss, impotency and occurrence of high-grade prostate tumours, it is important to seek for other potent and specific molecules with lower side effects. In the present work, we designed and synthesized steroids with the 3-keto-D4 moiety in the A-ring, as in the 5a-R substrate T, and with carboxamide, carboxyester or carboxylic acid functions at the C-17b position. The inhibitory 5a-R activity, in human prostate microsomes, as well as the anti-proliferative effects of the most potent compounds, in a human androgen-responsive prostate cancer cell line (LNCaP cells), were investigated. Our results showed that steroids 3, 4 and 5 are good RIs, which suggest that C-17b lipophylic amides favour 5a-R inhibition. Moreover, these steroids induce a decrease in cell viability of stimulated LNCaP cells, in a 5a-R dependent-manner, similarly to finasteride. ; The authors are grateful to Fundação para a Ciência e Tecnologia (FCT) for the strategic project PEst-OE/SAU/UI0177/2011 and for the PhD grants attributed to Cristina Amaral and Carla Varela (SFRH/ BD/48190/2008 and SFRH/BD/44872/2008, respectively). Sara C. Cunha is grateful to “Subprograma Ciência e Tecnologia do 3 Quadro Comunitário de Apoio” for grant SFRH/BPD/41854/2007. We also acknowledge the “Rede Nacional de RMN” (REDE/1517/ RMN/2005) for access to the facilities. This work was funded by FEDER Funds through the Operational Competitiveness Program- COMPETE and by National Funds through FCT under the project FCOMP-01-0124-FEDER-020970 (PTDC/QUI-BIQ/120319/2010).