Discovery of furyl/thienyl β-carboline derivatives as potent and selective PDE5 inhibitors with excellent vasorelaxant effect.

Abstract:

:Based on our previous studies and predictive docking results, furans and thiophenes were introduced to the privileged tetrahydro-β-carboline scaffold to generate more potent and selective PDE5 inhibitors. A total of 66 novel furyl/thienyl tetrahydro-β-carboline derivatives were designed, synthesized and evaluated for PDE5 inhibition. Tetrahydro-β-carboline-piperazinedione 19f and tetrahydro-β-carboline-hydantoin 26b with optimized pendant 5-ethylfuran/5-ethylthiophene were identified as the most potent PDE5 inhibitors, and showed high selectivity towards PDE5 versus other PDE isozymes, especially PDE6 and PDE11. Further vasorelaxant activity assessments revealed that these PDE5 inhibitors also exhibited significant angiectasis on the norepinephrine-precontracted 3rd-order mesenteric arteries (110-150 μm) via NO-sGC-cGMP pathway, implying their further application for the treatment of vascular diseases.

journal_name

Eur J Med Chem

authors

Zheng H,Wu Y,Sun B,Cheng C,Qiao Y,Jiang Y,Zhao S,Xie Z,Tan J,Lou H

doi

10.1016/j.ejmech.2018.09.028

subject

Has Abstract

pub_date

2018-10-05 00:00:00

pages

767-780

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(18)30800-6

journal_volume

158

pub_type

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