tadalafil, Cialis
Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules.

Sung BJ, Hwang KY, Jeon YH, Lee JI, Heo YS, Kim JH, Moon J, Yoon JM, Hyun YL, Kim E, Eum SJ, Park SY, Lee JO, Lee TG, Ro S, Cho JM.

Division of Drug Discovery, CrystalGenomics, Inc., Daedeok Biocommunity, Jeonmin-dong, Yuseong-gu, Daejeon, 305-390, South Korea.

Phosphodiesterases (PDEs) are a superfamily of enzymes that degrade the intracellular second messengers cyclic AMP and cyclic GMP. As essential regulators of cyclic nucleotide signalling with diverse physiological functions, PDEs are drug targets for the treatment of various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. Of the 12 PDE gene families, cGMP-specific PDE5 carries out the principal cGMP-hydrolysing activity in human corpus cavernosum tissue. It is well known as the target of sildenafil citrate (Viagra) and other similar drugs for the treatment of erectile dysfunction. Despite the pressing need to develop selective PDE inhibitors as therapeutic drugs, only the cAMP-specific PDE4 structures are currently available. Here we present the three-dimensional structures of the catalytic domain (residues 537-860) of human PDE5 complexed with the three drug molecules sildenafil, tadalafil (Cialis) and vardenafil (Levitra). These structures will provide opportunities to design potent and selective PDE inhibitors with improved pharmacological profiles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12955149&dopt=Abstract tadalafil Cialis



tadalafil, Cialis
The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 1: 5,6,11,11a-tetrahydro-1H-imidazo[1',5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione analogues.

Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Kirilovsky J, Hyafil F, Labaudiniere R.

Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 Avenue du Quebec, 91951 Les Ulis Cedex, France. acd9791 gsk.com

Starting from ethyl beta-carboline-3-carboxylate (beta-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-beta-carboline derivatives has been identified as a novel chemical class of potent and selective PDE5 inhibitors. Optimization of the side chain on the hydantoin ring of initial lead compound 2 and of the aromatic ring on position 5 led to the identification of compound 6e, a highly potent and selective PDE5 inhibitor, with greater selectivity for PDE5 vs PDE1-4 than sildenafil. Compound 6e demonstrated a long-lasting and significant blood pressure lowering effect after iv administration in the spontaneously hypertensive rat model but showed only moderate oral in vivo efficacy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14521414&dopt=Abstract tadalafil Cialis



tadalafil, Cialis
The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues.

Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudiniere R.

Laboratoire GlaxoSmithKline, Centre de Recherches, 25-27 Avenue du Quebec, 91951 Les Ulis Cedex, France.

Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC(50) = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14521415&dopt=Abstract tadalafil Cialis



tadalafil, Cialis
Tadalafil (Cialis) for men with erectile dysfunction.

Eardley I, Cartledge J.

Department of Urology, St James' University Hospital, Leeds, UK.

Tadalafil is an inhibitor of phosphodiesterase type 5, and is currently undergoing regulatory review in the US and in Europe. Its chemical structure is significantly different from sildenafil, and in vitro studies confirm significant potency for PDE5 inhibition, with little activity against most of the other isoforms of the enzyme including PDE6, which is the isoform of the enzyme found within the retina. The half-life of tadalafil is 17.5 hours and clinical studies suggest significant activity 24 hours post-dosing. As with sildenafil, efficacy depends upon a normal sexual stimulus, and the drug can taken be as required. Tadalafil is effective in the treatment of men with erectile dysfunction, and it appears to have a relatively mild side-effect profile, with no visual side-effects noted.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12074215&dopt=Abstract tadalafil Cialis



tadalafil, Cialis
Tadalafil: new preparation. Slightly more convenient, but poorly assessed in organic disorders.

[No authors listed]

(1) The standard oral treatment for erectile dysfunction is sildenafil, a type 5 phosphodiesterase inhibitor, whether the underlying problem is organic (for example, post prostatectomy or spinal cord damage) or psychological. (2) Another inhibitor of the same type, tadalafil, has been available in France since early 2003. (3) At 10 mg to 20 mg, tadalafil is more effective than placebo, including in diabetic patients. But placebo-controlled trials have included few patients with a history of total prostatectomy, spinal cord damage, or sildenafil failure. One trial, which was not published in detail, reported that the effects last more than 12 hours. But the European Medicines Evaluation Agency considered that the reported data did not support this conclusion. There was no significant difference between active treatment and placebo groups after 12 hours. The risk-benefit ratio of long term treatment with tadalafil is unknown. (4) The two available comparative trials do not rule out the possibility that tadalafil is less effective than sildenafil. (5) Known adverse effects and drug interactions are similar in both tadalafil and sildenafil. Both drugs are contraindicated in patients using nitrate derivatives, because of a risk of abrupt hypotension. (6) Unlike sildenafil, administration of tadalafil does not retard its action. (7) In practice, sildenafil remains the first line option for treating erectile dysfunction with an organic cause. Tadalafil is slightly easier to use.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14986690&dopt=Abstract tadalafil Cialis