Avanafil for the treatment of erectile dysfunction: initial data and clinical key properties

Abstract

Orally active, selective inhibitors of phosphodiesterase type 5 (PDE 5, cyclic GMP PDE), such as sildenafil, tadalafil and vardenafil, are currently the first-choice treatment options for the clinical management of erectile dysfunction (ED) of various etiologies and severities. However, a significant number of patients remain dissatisfied with the available therapies due a lack of efficacy or discomfort arising from adverse events. Several new PDE5 inhibitors, among which are avanafil (TA-1790), lodenafil, mirodenafil, udenafil, SLX-2101, JNJ-10280205 and JNJ-10287069, have recently been approved and introduced into the market or are in the final stages of their clinical development. Avanafil (marketed in the US under the brand name STENDRA(™)) has been developed by VIVUS Inc. (Mountain View, CA, USA) and has recently received approval from the US Food and Drug Administration (FDA) for use in the treatment of male ED. The drug has demonstrated improved selectivity for PDE5, is rapidly absorbed after oral administration with a fast onset of action and a plasma half-life that is comparable to sildenfil and vardenafil. In phase II and phase III clinical trials that included a large number of patients, avanafil has been shown to be effective and well tolerated. Owing to its favorable pharmacodynamic and pharmacokinetic profile, avanafil is considered as a promising new option in the treatment of ED. The present article summarizes the initial data and clinical key properties of avanafil.

Keywords: PDE5 inhibitors; avanafil; erectile dysfunction; oral pharmacotherapy.

Figure 1.

Structural formula of avanafil. In order to bind effectively to the catalytic site of the PDE5, a selective inhibitor has to comprise three major structural principles: a guanine-like base, a ribose- or desoxyribose-like system and, finally, a phosphate diester-like bond. In the avanafil molecule, the central structure is formed by a nitrogen derivative of a pyrimidine carboxamide where the nitrogen atom of the amide is bound to a pyrimidinylmethyl group. It seems likely that the ribose (sugar)-phosphate component is represented by a cyclic chloromethoxybenzylamino structure; in this case, the Cl-atom and the methoxy ligand resemble the phosphate group seen in, for example, sildenafil and vardenafil.