An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies

Biochemical Pharmacology

Volumn 75, Issue 9, 2008, Pages 1717-1728

  Chen, Gong ^a   Wang, Huanchen ^b   Robinson, Howard ^c   Cai, Jiwen ^a   Wan, Yiqian ^a   Ke, Hengming ^b  

^a Sun Yat Sen Univereity   (China)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^c BROOKHAVEN NATIONAL LABORATORY   (United States)

Author keywords

Crystal structure; Phosphodiesterase (PDE); Sildenafil; Viagra

Indexed keywords

5 [2 ETHOXY 5 (SULFAMOYL) 3 THIENYL] 1 METHYL 3 PROPYL 1,6 DIHYDRO 7H PYRAZOLO[4,3 D]PYRIMIDIN 7 ONE; GLUTAMINE; ISOBUTYLMETHYLXANTHINE; PHENYLALANINE; PHOSPHODIESTERASE V INHIBITOR; SILDENAFIL; SULFONAMIDE; TADALAFIL; UDENAFIL; UK 122764; UNCLASSIFIED DRUG; VARDENAFIL;

ARTICLE; CONFORMATIONAL TRANSITION; CRYSTAL STRUCTURE; DRUG SYNTHESIS; ERECTILE DYSFUNCTION; HYDROGEN BOND; PHARMACOPHORE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; STRUCTURE ACTIVITY RELATION;

BINDING SITES; CLONING, MOLECULAR; CRYSTALLOGRAPHY, X-RAY; CYCLIC NUCLEOTIDE PHOSPHODIESTERASES, TYPE 5; ESCHERICHIA COLI; HUMANS; HYDROPHOBICITY; MODELS, MOLECULAR; MOLECULAR STRUCTURE; PIPERAZINES; PROTEIN BINDING; PROTEIN CONFORMATION; PURINES; STRUCTURE-ACTIVITY RELATIONSHIP; SULFONES;

EID: 41949117255     PISSN: 00062952     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bcp.2008.01.019     Document Type: Article

References (40)

1. Bender A.T., and Beavo J.A. Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use. Pharmacol Rev 58 (2006) 488-520
2. Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) superfamily: a new target for the development of specific therapeutic agents. Pharmacol Ther 109 (2006) 366-398
3. Omori K., and Kotera J. Overview of PDEs and their regulation. Circ Res 100 (2007) 309-327
4. Ke H., and Wang H. Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. Curr Top Med Chem 7 (2007) 391-403
5. Conti M., and Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Ann Rev Biochem 76 (2007) 481-511
6. Truss M.C., Stief C.G., Uckert S., Becker A.J., Wafer J., Schultheiss D., et al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: from bench to bedside. World J Urol 19 (2001) 344-350
7. Rotella D.P. Phosphodiesterase 5 inhibitors: current status and potential applications. Nat Rev Drug Discov 1 (2002) 674-682
8. Schrör K. The pharmacology of cilostazol. Diabetes Obes Metab 4 suppl. 2 (2002) S14-S19
9. Abdel-Hamid I.A. Phosphodiesterase 5 inhibitors in rapid ejaculation: potential use and possible mechanisms of action. Drugs 64 (2004) 13-26
10. Lipworth B.J. Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease. Lancet 365 (2005) 167-175
11. Castro A., Jerez M.J., Gil C., and Martinez A. Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: advances in the development of specific phosphodiesterase inhibitors. Med Res Rev 25 (2005) 229-244
12. Houslay M.D., Schafer P., and Zhang K.Y. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today 10 (2005) 1503-1519
13. Blokland A., Schreiber R., and Prickaerts J. Improving memory: a role for phosphodiesterases. Curr Pharm Des 12 (2006) 2511-2523
14. Menniti F.S., Faraci W.S., and Schmidt C.J. Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5 (2006) 660-670
15. Galie N., Ghofrani H.A., Torbicki A., Barst R.J., Rubin L.J., Badesch D., et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 353 (2005) 2148-2157
16. Salem E.A., Kendirci M., and Hellstrom W.J. Udenafil a long-acting PDE5 inhibitor for erectile dysfunction. Curr Opin Invest Drugs 7 (2006) 661-669
17. Supuran C.T., Mastrolorenzo A., Barbaro G., and Scozzafava A. Phosphodiesterase 5 inhibitors-drug design and differentiation based on selectivity, pharmacokinetic and efficacy profiles. Curr Pharm Des 12 (2006) 3459-3465
18. Stehlik J., and Movsesian M.A. Inhibitors of cyclic nucleotide phosphodiesterase 3 and 5 as therapeutic agents in heart failure. Expert Opin Invest Drugs 15 (2006) 733-742
19. Palmer M.J., Bell A.S., Fox D.N., and Brown D.G. Design of second generation phosphodiesterase 5 inhibitors. Curr Top Med Chem 7 (2007) 405-419
20. Zhu B., and Strada S.J. The novel functions of cGMP-specific phosphodiesterase 5 and its inhibitors in carcinoma cells and pulmonary/cardiovascular vessels. Curr Top Med Chem 7 (2007) 437-454
21. Sung B.J., Hwang K.Y., Jeon Y.H., Lee J.I., Heo Y.S., Kim J.H., et al. Structure of the catalytic domain of human phosphodiesterase 5 with bound drug molecules. Nature 425 (2003) 98-102
22. Huai Q., Liu Y., Francis S.H., Corbin J.D., and Ke H. Crystal structures of phosphodiesterases 4 and 5 in complex with inhibitor IBMX suggest a conformation determinant of inhibitor selectivity. J Biol Chem 279 (2004) 13095-13101
23. Zhang K.Y., Card G.L., Suzuki Y., Artis D.R., Fong D., Gillette S., et al. Glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Mol Cell 15 (2004) 279-286
24. Card G.L., England B.P., Suzuki Y., Fong D., Powell B., Lee B., et al. Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 12 (2004) 2233-2247
25. Wang H., Liu Y., Huai Q., Cai J., Zoraghi R., Francis S.H., et al. Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development. J Biol Chem 281 (2006) 21469-21479
26. Rotella D.P., Sun Z., Zhu Y., Krupinski J., Pongrac R., Seliger L., et al. N-3-Substituted imidazoquinazolinones: potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction. J Med Chem 43 (2000) 1257-1263
27. Mader M.M., Shih C., Considine E., Dios A.D., Grossman C.S., Hipskind P.A., et al. Acyl sulfonamide anti-proliferatives. Part 2. Activity of heterocyclic sulfonamide derivatives. Bioorg Med Chem Lett 15 (2005) 617-620
28. El-Abadelah M.M., Sabri S.S., Khanfar M.A., Voelter W., Abdel-Jalil R.J., Maichle-Mossmer C., et al. Synthesis and properties of a-thiagra. A substituted 5-(2-thienyl)pyrazolo[4,3-d]pyrimidin-7-one bioisostere of Viagra. Heterocycles 53 (2000) 2643-2652
29. Dale D.J., Dunn P.J., Golightly C., Hughes M.L., Levett P.C., Pearce A.K., et al. The chemical development of the commercial route to sildenafil: a case history. Org Process Res Develop 4 (2000) 17-22
30. Keegstra M.A., Peters T.H.A., and Brandsma L. Copper(I) halide catalyzed synthesis of alkyl aryl and alkyl heteroaryl ethers. Tetrahedron 48 (1992) 3633-3652
31. El Kassmi A., Fache F., and Lemaire M.A. convenient synthesis of 3-fluorothiophene. Synth Commun 24 (1994) 95-101
32. 2) bond formation: N-arylation of aromatic and unsaturated nitrogen and the reductive elimination chemistry of palladium azolyl and methyleneamido complexes. J Am Chem Soc 120 (1998) 827-828
33. Wu X., Wan Y., Mahalingam A.K., Murugaiah A.M.S., Plouffe B., Botros M., et al. Selective angiotensin II AT2 receptor agonists: arylbenzylimidazole structure-activity relationships. J Med Chem 49 (2006) 7160-7168
34. Otwinowski Z., and Minor W. Processing of X-ray diffraction data collected in oscillation mode. Methods Enzymol 276 (1997) 307-326
35. Navaza J., and Saludjian P. AMoRe: an automated molecular replacement program package. Methods Enzymol 276 (1997) 581-594
36. Jones T.A., Zou J.-Y., Cowan S.W., and Kjeldgaard M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Crystallogr A 47 (1991) 110-119
37. Brünger A.T., Adams P.D., Clore G.M., DeLano W.L., Gros P., Grosse-Kunstleve R.W., et al. Crystallography & NMR system: a new software suite for macromolecular structure determination. Acta Crystallogr D 54 (1998) 905-921
38. Wang H., Ye M., Robinson H., Francis S.H., and Ke H. Conformational variations of both PDE5 and inhibitors provide the structural basis for the physiological effects of vardenafil and sildenafil. Mol Pharmacol 73 (2008) 104-110
39. Turko I.V., Francis S.H., and Corbin J.D. Hydropathic analysis and mutagenesis of the catalytic domain of the cGMP-binding cGMP-specific phosphodiesterase (PDE5). cGMP versus cAMP substrate selectivity. Biochemistry 37 (1998) 4200-4205
40. Turko I.V., Ballard S.A., Francis S.H., and Corbin J.D. Inhibition of cyclic GMP-binding cyclic GMP-specific phosphodiesterase (Type 5) by sildenafil and related compounds. Mol Pharmacol 56 1 (1999) 124-130