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1 . Frey MK, Lang I. Tadalafil for the treatment of pulmonary arterial hypertension. Expert Opin Pharmacother. 2012 Apr;13(5):747-55.
Abstract
INTRODUCTION: Pulmonary arterial hypertension (PAH) is a progressive occlusive disease affecting the pulmonary vasculature; it carries a poor prognosis. Because right ventricular failure is the key feature of deterioration in PAH patients, vasodilator treatments relieving right ventricular afterload have gained ground in the treatment of this disorder. Phosphodiesterase-5 inhibitors are effective and well tolerated vasodilators that were originally developed for erectile dysfunction. Tadalafil , the first once-daily drug of this class, was approved by the USFDA in May 2009 for the treatment of patients suffering from PAH. AREAS COVERED: This review outlines the currently available data about tadalafil and its effects in patients with PAH. It also presents evidence from recent clinical trials of tadalafil and discusses potential improvements over existing therapy options and their impact on current treatment strategies. EXPERT OPINION: Tadalafil is an efficacious drug with a favorable side-effect profile and convenient mode of administration. More studies are needed to analyze its impact on survival and to substantiate its role in an upfront combination treatment strategy.
2 . Porst H, Hell-Momeni K, Büttner H. Chronic PDE-5 inhibition in patients with erectile dysfunction – a treatment approach using tadalafil once-daily. Expert Opin Pharmacother. 2012 Jul;13(10):1481-94.
Abstract
INTRODUCTION: Tadalafil distinguishes itself from other available phosphodiesterase type 5 (PDE-5) inhibitors by its half-life of ? 17.5 h, which results in erectile responsiveness for up to 36 h after a single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but several studies have been able to demonstrate that tadalafil, given once-daily in low doses, is both highly effective and well tolerated. AREAS COVERED: This paper reviews the current evidence for efficacy and safety of tadalafil, as well as the rationale for offering low-dose tadalafil once-daily to patients with erectile dysfunction as an alternative to on-demand treatment. EXPERT OPINION: Tadalafil once-daily provides efficacy comparable to on-demand dosing regimens with PDE-5 inhibitors, is well tolerated and allows patients and their partners to disconnect the administration of medication from sexual activity, thereby enabling them to return to the sex-life they had before the onset of erectile dysfunction.
3 . Daugan, Alain; Grondin, Pascal; Ruault, Cecile et al. 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 analogue. Journal of Medicinal Chemistry (2003), 46(21), 4533-4542.
Abstract
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).
4 . Beghyn, Terence; Hounsou, Candide; Deprez, Benoit P. PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil. Bioorganic & Medicinal Chemistry Letters (2007), 17(3), 789-792.
Abstract
A method to access totally new analogues of tadalafil was explored. The Buchwald reaction was adapted and used to replace the methyl group of tadalafil by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds.
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