The first evidence of the existence of renin was presented over 100 years ago. However, the importance of renin and the renin-angiotensin system in the pathogenesis of cardiovascular disease was only fully realized in the 1970s. It was another 20 years before the first inhibitors of renin were available for clinical research. Here, we describe the discovery and development of aliskiren, an orally active renin inhibitor, which became the first drug in its class to receive regulatory approval. In 2007, it was approved for the treatment of hypertension by the US Food and Drug Administration and the European Medicines Agency.
The protected serine aldehyde 10 was converted to the crystalline N-Boc-protected sphingosines 6 9 by a three-step reaction sequence. Compound 10 was transformed with high diastereoselectivity (95 %) either to the eryrhro-or threo-alkynols, 17 and 18, respectively. The eryfhro-isomer 17 is formed by the addition to 10 of lithium pentadecyne 16 in THFiHMPT at -78", whereas the corresponding ihreo-isomer 18 is produced in the presence of ZnBr, in Et,O. Deprotection of the acetal moiety afforded 1,3-diols 19 and 20. These diols were selectively reduced with Red-A1 to the (E)-sphingosines 6 and 8, or the (Z)-isomers 7 and 9 by partial hydrogenation over Lindlar's catalyst. Cleavage of the N-Boc group and further transformation to ceramides were readily achieved as demonstrated by the conversion of 6 to N-octadecanoyl-~-erythro-sphingosine 5.
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