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 - PubMed (original) (raw)
. 2003 Oct 9;46(21):4525-32.
doi: 10.1021/jm030056e.
Affiliations
- PMID: 14521414
- DOI: 10.1021/jm030056e
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
Alain Daugan et al. J Med Chem. 2003.
Abstract
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.
Similar articles
- 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, Labaudinière R. Daugan A, et al. J Med Chem. 2003 Oct 9;46(21):4533-42. doi: 10.1021/jm0300577. J Med Chem. 2003. PMID: 14521415 - Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity.
Ahn HS, Bercovici A, Boykow G, Bronnenkant A, Chackalamannil S, Chow J, Cleven R, Cook J, Czarniecki M, Domalski C, Fawzi A, Green M, Gündes A, Ho G, Laudicina M, Lindo N, Ma K, Manna M, McKittrick B, Mirzai B, Nechuta T, Neustadt B, Puchalski C, Pula K, Zhang H, et al. Ahn HS, et al. J Med Chem. 1997 Jul 4;40(14):2196-210. doi: 10.1021/jm9608467. J Med Chem. 1997. PMID: 9216839 - Optimization of purine based PDE1/PDE5 inhibitors to a potent and selective PDE5 inhibitor for the treatment of male ED.
Boyle CD, Xu R, Asberom T, Chackalamannil S, Clader JW, Greenlee WJ, Guzik H, Hu Y, Hu Z, Lankin CM, Pissarnitski DA, Stamford AW, Wang Y, Skell J, Kurowski S, Vemulapalli S, Palamanda J, Chintala M, Wu P, Myers J, Wang P. Boyle CD, et al. Bioorg Med Chem Lett. 2005 May 2;15(9):2365-9. doi: 10.1016/j.bmcl.2005.02.083. Bioorg Med Chem Lett. 2005. PMID: 15837326 - Pharmacology and drug interaction effects of the phosphodiesterase 5 inhibitors: focus on alpha-blocker interactions.
Kloner RA. Kloner RA. Am J Cardiol. 2005 Dec 26;96(12B):42M-46M. doi: 10.1016/j.amjcard.2005.07.011. Epub 2005 Dec 5. Am J Cardiol. 2005. PMID: 16387566 Review. - Potency, selectivity, and consequences of nonselectivity of PDE inhibition.
Bischoff E. Bischoff E. Int J Impot Res. 2004 Jun;16 Suppl 1:S11-4. doi: 10.1038/sj.ijir.3901208. Int J Impot Res. 2004. PMID: 15224129 Review.
Cited by
- Mild and efficient cyanuric chloride catalyzed Pictet-Spengler reaction.
Sharma A, Singh M, Rai NN, Sawant D. Sharma A, et al. Beilstein J Org Chem. 2013 Jun 26;9:1235-42. doi: 10.3762/bjoc.9.140. Print 2013. Beilstein J Org Chem. 2013. PMID: 23843919 Free PMC article. - Development of Therapeutics That Induce Mitochondrial Biogenesis for the Treatment of Acute and Chronic Degenerative Diseases.
Cameron RB, Beeson CC, Schnellmann RG. Cameron RB, et al. J Med Chem. 2016 Dec 8;59(23):10411-10434. doi: 10.1021/acs.jmedchem.6b00669. Epub 2016 Sep 27. J Med Chem. 2016. PMID: 27560192 Free PMC article. Review. - Synthesis, molecular modeling and biological evaluation of novel tadalafil analogues as phosphodiesterase 5 and colon tumor cell growth inhibitors, new stereochemical perspective.
Abadi AH, Gary BD, Tinsley HN, Piazza GA, Abdel-Halim M. Abadi AH, et al. Eur J Med Chem. 2010 Apr;45(4):1278-86. doi: 10.1016/j.ejmech.2009.10.046. Eur J Med Chem. 2010. PMID: 20206015 Free PMC article. - Pharmacological importance of optically active tetrahydro-β-carbolines and synthetic approaches to create the C1 stereocenter.
Laine AE, Lood C, Koskinen AM. Laine AE, et al. Molecules. 2014 Jan 27;19(2):1544-67. doi: 10.3390/molecules19021544. Molecules. 2014. PMID: 24473212 Free PMC article. Review. - Epipolythiodioxopiperazine-Based Natural Products: Building Blocks, Biosynthesis and Biological Activities.
Huber EM. Huber EM. Chembiochem. 2022 Dec 5;23(23):e202200341. doi: 10.1002/cbic.202200341. Epub 2022 Sep 15. Chembiochem. 2022. PMID: 35997236 Free PMC article. Review.
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Chemical Information