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
- 17 September 2003
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 46 (21), 4525-4532
- https://doi.org/10.1021/jm030056e
Abstract
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.Keywords
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