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
Starting from ethyl β-carboline-3-carboxylate (β-CCE), 1, a modest inhibitor of type 5 phosphodiesterase (PDE5), a series of functionalized tetrahydro-β-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.
Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier De Gouville, Anne-Charlotte,Coste, Hervé,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinière, Richard
p. 4525 - 4532
(2007/10/03)
Chemical compounds
Compounds of the general structural formula and use of the compounds and salts and solvates thereof, as therapeutic agents.
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(2008/06/13)
Synthese der Ester der 1-Pyridyl-β-carbolin-3-carbonsaeure
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Cegla, M.,Duszynska, Beata,Misztal, S.
p. 510
(2007/10/02)
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