5/17/2012 09:14:00 pm
Unknown
On April 27th, the FDA approved Avanafil (tradename: Stendra; Research Code: TA-1790), a phosphodiesterase 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED). ED
is a sexual dysfunction characterized by the inability to produce an
erection of the penis. The physiologic mechanism of penile erection
involves the release of nitric oxide in the corpus cavernosum during
sexual stimulation, which in turn activates the enzyme guanylate cyclase, resulting in increased levels of cyclic guanosine monophosphate (cGMP).
cGMP produces relaxation of smooth muscle tissues, which in the corpus
cavernosum results in vasodilation and increased blood flow. Avanafil
(PubChem: CID9869929, ChemSpider: 8045620) enhances the relaxant effects of cGMP by selectively inhibiting PDE5 (ChEMBL: CHEMBL1827; Uniprot: O76074), an enzyme responsible for the degradation of cGMP.
Other PDE5 inhibitors are already available on the
market and these include Sildenafil (approved in 1998; tradename:
Viagra, Revatio; ChEMBL: CHEMBL192), Tadalafil (approved in 2003; tradename: Cialis; ChEMBL: CHEMBL779) and Vardenafil (approved in 2003; tradename: Levitra; ChEMBL: CHEMBL1520). These other PDE5 inhibitors are also approved for the treatment of pulmonary arterial hypertension (PAH).
PDE5 is an 875 amino acid-long enzyme (EC=3.1.4.35), belonging to the cyclic nucleotide phosphodiesterase family (PFAM: PF00233).
Several crystal structures of PDE5 are now available. The catalytic
domain of human PDE5 complexed with sildenafil is shown below (PDBe:1tbf)
Preclinical studies have shown that
Avanafil strongly inhibits PDE5 (half maximal inhibitory concentration =
5.2 nM) in a competitive manner and is 100-fold more potent for PDE5
than PDE6, which is found in the retina and is responsible for
phototransduction. Also, Avanafil has shown higher selectivity
(120-fold) against PDE6 than Sildenafil (16-fold) and Vardenafil
(21-fold), and high selectivity (>10 000-fold) against PDE1 compared
with Sildenafil (380-fold) and Vardenafil (1000-fold).
Avanafil has also been reported
to be a faster-acting drug than Sildenafil, with an onset of action as
little as 15 minutes as opposed to 30 minutes for the other drugs.
Avanafil is a synthetic small molecule, with one chiral center. Avanafil has
a molecular weight of 345.21 Da, an ALogP of 2.16, 3 hydrogen bond
donors and 9 hydrogen bond acceptors and thus fully rule-of-five
compliant. (IUPAC: 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-[(2S)-2-(hydroxymethyl)-pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl)pyrimidine-5-carboxamide;
Canonical Smiles:
COC1=C(C=C(C=C1)CNC2=NC(=NC=C2C(=O)NCC3=NC=CC=N3)N4CCC[C@H]4CO)Cl;
InChI: InChI=1S/C23H26ClN7O3/c1-34-19-6-5-15(10-18(19)24)11-27-21-17(22(33)28-
Avanafil is rapidly absorbed after oral administration, with a median Tmax
of 30 to 45 minutes in the fasted state and 1.12 to 1.25 hours when
taken with a high fat meal. Avanafil is approximately 99% bound to
plasma proteins and has been found to not accumulate in plasma. It is
predominantely cleared by hepatic metabolism, mainly by CYP3A4 enzyme
and to a minor extent by CYP2c isoform. The plasma concentrations of the
major metabolites, M4 and M16, are approximately 23% and 29% of that of
the parent compound, respectively. The M4 metabolite accounts for approximately 4% of the pharmacologic activity of Avanafil, with an in vitro
inhibitory potency for PDE5 of 18% of that of Avanafil. The M16
metabolite has been found inactive against PDE5. After oral
administration, Avanafil is excreted as metabolites mainly in the feces
(approximately 62% of administrated dose) and to a lesser extent in the
urine (approximately 21% of the administrated dose). Avanafil has a
terminal elimination half-life (t1/2) of approximately 5
hours, which is comparable to that of Sildenafil (3-4h) and Vardenafil
(4-5h), but very short relative to the very long half-life of Tadalafil
(17.5h).
13-20-25-7-3-8-26-20)12-29-23(30-21)31-9-2-4-16(31)14-32/h3,5-8,10,12,
16,32H,2,4,9,11,13-14H2,1H3,(H,28,33)(H,27,29,30)/t16-/m0/s1)
The recommended starting dose of Avanafil is 100 mg and should be taken
orally as needed approximately 30 minutes before sexual activity.
Depending on individual efficacy and tolerability, the dose can be
varied to a maximum dose of 200 mg or decreased to 50 mg. The lowest
dose that provides efficacy should be used. The maximum recommended
dosing frequency is once per day.
Wikipedia: Avanafil
