The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid Tmax SSRI

Abstract

With the realisation that selective serotonin reuptake inhibitors (SSRIs) are effective in treating premature ejaculation (PE), a project was started to identify a short T1/2, rapid Tmax compound suitable for on-demand dosing. It was anticipated that the key to achieving such a profile was to reduce the volume of distribution (VD) relative to the marketed SSRI antidepressants, which have high VD, late Tmax and long T1/2. Initial work focused on reducing VD in the sertraline template 3. While a moderate reduction in VD was achieved and sulfonamide 14 (UK-373911) was identified as a clinical candidate, this strategy was ultimately unsuccessful as 14 had an extremely long T1/2 in man. The key to finding compounds with the properties we desired was to switch to a diphenyl ether template which had an inherently lower VD. Early analogues had the desired low VD, and resulting short T1/2 and rapid Tmax, but gave circulating active metabolites. Incorporation of a metabolically vulnerable thioether resulted in metabolism to essentially inactive sulfoxide metabolites and led to the identification of the sulfonamide 63 (UK-390957) as a clinical candidate. Profiling in man showed that we had achieved our desired target of a rapid Tmax and short T1/2 and 63 was progressed to Phase II studies for the treatment of PE. That structure can be more important than physicochemical properties in determining volume is supported by the fact that the SSRI dapoxetine, marketed for the treatment of PE, has a low volume, comparable with 63, despite being significantly more lipophilic.