A Novel Series of Potent and Selective PDE5 Inhibitors with Potential for High and Dose-Independent Oral Bioavailability

Abstract

Sildenafil (5-[2-ethoxy-5-(4-methyl-1-piperazinylsulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one), a potent and selective phosphodiesterase type 5 (PDE5) inhibitor, provided the first oral treatment for male erectile dysfunction. The objective of the work reported in this paper was to combine high levels of PDE5 potency and selectivity with high and dose-independent oral bioavailability, to minimize the impact on the C(max) of any interactions with coadministered drugs in the clinic. This goal was achieved through identification of a lower clearance series with a high absorption profile, by replacing the 5'-piperazine sulfonamide in the sildenafil template with a 5'-methyl ketone. This novel series provided compounds with low metabolism in human hepatocytes, excellent caco-2 flux, and the potential for good aqueous solubility. The in vivo oral and iv pharmacokinetic profiles of example compounds confirmed the high oral bioavailability predicted from these in vitro screens. 5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (2) was selected for progression into the clinic.

Towards a decade of detecting new analogues of sildenafil, tadalafil and vardenafil in food supplements: A history, analytical aspects and health risks

“…According to scientific literature, two analogues of the analogues were ultimately in the race of becoming the active ingredient in Viagra ® (Fig. 2) [41,42]. The analogue that was selected after clinical evaluation became known as sildenafil.…”

“…The analogue that was selected after clinical evaluation became known as sildenafil. The analogue that was discarded was of the acetildenafil-type ('morpholino-acetildenafil') and reportedly had undesirable properties [41]. The nature of these properties was not described.…”

“…Acetildenafil is associated with an increased risk of visual disturbances [23,83,84]. This is because acetildenafil is equipotent to sildenafil but lacks its PDE-5/PDE-6 selectivity [41].…”

“…Interestingly, the analogue morpholino-acetildenafil that failed in the clinical development of Viagra ® is also a non-selective PDE-5/PDE-6 inhibitor (Fig. 2) [41]. Whether this was due to the lack of selectivity is not reported.…”

Toward a New Generation of PDE5 Inhibitors through Advances in Medicinal Chemistry

“…Along with the challenges associated with modulating half-life, little was known about how to improve PDE6 selectivity, let alone the potential for staying clear of PDE7-11 activity. Pfizer has published on three chemical templates addressed in their postsildenafil research efforts in seeking novel PDE5 inhibitors [28][29][30]. The initial, conservative, second-generation agents focused on staying close to sildenafil's pyrazolopyrimidinone template.…”