Nucleic acids U 0700Synthesis of Novel Tadalafil Analogues and Their Evaluation as Phosphodiesterase Inhibitors and Anticancer Agents. -Two series of novel β-carboline derivatives, electronically similar to tadalafil, are synthesized starting from D-or L-tryptophane, respectively. Compound (VII) and its precursor (IV) show the most potent PDE5 and HT29 growth inhibitory activity. -(ABADI*, A. H.; ABOUEL-ELLA, D. A.; AHMED, N. S.; GARY, B. D.; THAIPARAMBIL, J. T.; TINSLEY, H. N.; KEETON, A. B.; PIAZZA, G. A.; Arzneim.-Forsch. 59 (2009) 8, 415-421; Dep. Pharm. Chem., Fac. Pharm. Biotechnol., German Univ., Cairo, Egypt; Eng.) -C. Cyrus 52-202

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EPI-X4 is a natural peptide antagonist of CXCR4, an established drug target in inflammatory diseases and cancer. Advanced derivatives of EPI-X4, such as EPI-X4 JM#21, have shown promising therapeutic effects in animal models of CXCR4-associated diseases but suffer from poor stability in blood. We here aimed to design and characterize EPI-X4 analogs that effectively antagonize CXCR4 while remaining stable in human plasma. We found that EPI-X4 analogs are stable against degradation by endopeptidases. However derivatives are are prone to degradation by exopeptidases which target the peptides’ N- but not the C-terminus. Modifications of the peptide N-terminus by introducing D-amino acids or acetyl residues resulted in EPI-X4 derivatives with greatly enhanced plasma stability. The identified lead candidates EPI-X4 JM#29, JM#173, and JM#174, which contain D-amino acids L or I at position 1, were as active in binding and antagonizing CXCR4 as EPI-X4 JM#21, and remained active even after 8 hours of incubation in plasma. Molecular dynamics simulations showed that the binding mode of these stabilized EPI-X4 derivatives to CXCR4 is similar to the binding of JM#21. The peptides establish conserved interactions with acidic residues in the minor subpocket and the extracellular loops 1 and 2 of the receptor. None of the novel EPI-X4 leads showed any signs of toxicity in zebrafish embryos, paving the way for further evaluation of the pharmacokinetic and therapeutic properties of this new generation of EPI-X4 analogs in rodent models.

Tadalafil, Cialis, Eli Lilly & Co./ICOS, (6R,12aR)‐6‐(1,3‐benzodioxol‐5‐yl)‐2‐methyl‐2,3,6,7,12,12a‐hexahydropyrazino[1′,2′:1,6] pyrido[3,4‐b]indole‐1,4‐dione, was first discovered in 2003. It was reported to have high diastereospecificity for phosphodiesterase 5 (PDE5) inhibitions. The cis‐(6R, 12aR) enantiomer is the most active enantiomer. Tadalafil showed PDE5 inhibition with IC50 = 5 nM. It possesses high selectivity for PDE5 versus PDE1‐4 and PDE6. Tadalafil is more selective to PDE5 against PDE6 whereas sildenafil, another commercially available PDE5 inhibitor shows similar potencies to inhibit PDE5 and PDE6. Tadalafil is used for the treatment of male erectile dysfunction (MED), prostatic benign hyperplasia (PBH) signs and symptoms, and pulmonary arterial hypertension (PAH). Adcirca, another name for tadalafil, is used to treat PAH and improve exercise capacity. Recent clinical studies suggest the use of tadalafil for nonurological applications, including circulatory disorders (ischemia injury, myocardial infarction, cardiac hypertrophy, cardiomyopathy, heart failure, and stroke), neurodegenerative disorders, and cognitive impairment conditions. This review discusses tadalafil and its analogues reported in the past 15 years. It discusses synthetic pathways, structural activity relationships, existing and future pharmacological indications of tadalafil and its analogues. This work can help medicinal chemists developing novel PDE5 inhibitors with wider therapeutic indications.

Starting from tadalafil as a template, a series of functionalized tetrahydro-b-carboline derivatives have been prepared and identified as novel potent and selective PDE5 inhibitors. Replacing the 3,4-methylenedioxyphenyl at position 6 of tadalafil, together with elongation of the N2-methyl substituent and manipulation of the stereochemical aspects of the two chiral carbons led to the identification of compound XXI, a highly potent PDE5 inhibitor (IC50 = 3 nM). Compound XXI was also highly selective for PDE5 versus PDE3B, PDE4B, and PDE11A, with a selectivity index of 52 and 235 towards PDE5 rather than PDE11 with both cAMP and cGMP as substrate, respectively.