The Discovery of UK-390957: the Challenge of Targeting a Short Half-life, Rapid T SSRI - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 163

regime when treating sexual dysfunctions, as continued ecacy allows for a
more spontaneous sexual life. 36,37 Secondly, while the short half-life could
result in an improved side-effect profile due to reduced drug exposure, the
ecacy of on-demand treatment has been questioned. 9,38 The argument is that
on-demand treatment does not lead to the adaptive changes in brain chemistry
that are seen with chronic (daily) treatment, which may be required for max-
imum ecacy. There is also some data to suggest that on-demand dosing with
classical SSRIs such as paroxetine may show reduced e cacy relative to
chronic dosing. 2
Dapoxetine has shown ecacy in clinical trials for the on-demand treatment
of PE, 4,39 and was approved for this indication under the trade name Priligy t
by several European countries in 2009. An earlier filing in the USA, however,
was given a ''not approvable'' letter by the FDA in 2005. 40
7.6 Summary
Initial work to identify a short t 1/2 , rapid T max SSRI focused on reducing V D in
the tetrahydronaphthalene template 3. While a moderate reduction in V D was
achieved, this strategy was ultimately unsuccessful as sulfonamide UK-373911
has an extremely long t 1/2 in man. The key to finding compounds with the
properties we desired was to switch to the diphenyl ether template, which has an
inherently lower V D . Early analogues had the desired low V D , and resulting
short t 1/2 and rapid T max , but gave circulating active metabolites. Incorporation
of a metabolically vulnerable sulfide resulted in metabolism to essentially
inactive sulfoxide metabolites and led to the identification of the sulfonamide
UK-390957 as a clinical candidate. Profiling in man showed that we had
achieved our desired target of a rapid T max and short t 1/2 and UK-390957 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 has a low volume of distribution,
comparable to that of UK-390957, despite being significantly more lipophilic.
References
1. A. Hemeryck and F. M. Belpaire, Curr. Drug Metab., 2002, 3, 13, and
references cited therein.
2. A. J. Moreland and E. H. Makela, Ann. Pharmacother., 2005, 39, 1296.
3. M. D. Waldinger, Expert Opin. Emerging Drugs, 2006, 11, 99.
4. K. Patel and W. J. G. Hellstrom, Curr. Opin. Invest. Drugs, 2009, 10,681.
5. American Psychiatry Association, Diagnostic and Statistical Manual of
Mental Disorders, 4th edn, American Psychiatric Association, Washington,
1994, p. 509.
6. M. E. Metz, J. Sex Marital Ther., 1997, 23,3.
7. E. O. Laumann, A. Paik and R. C. Rosen, J. Am. Med. Assoc., 1999, 281, 537.
8. Y. Huang and W. A. Williams, Expert Opin. Ther. Pat., 2007, 17, 889.