A novel access to arylated and heteroarylated beta-carboline based PDE5 inhibitors.
Starting from a previously reported lead compound GR30040X (a hydantoin tetrahydro-β-carboline derivative with a 4- pyridinyl ring at C- 5), a series of structurally related tetrahydro-β-carboline derivatives were prepared. The tetrahydro-β-carboline skeleton was fused either to a hydantoin or to a piperazindione ring, the pendant aryl group attached to C-5 or C-6 was changed to a 3, 4-dimethoxyphenyl or a 3-pyridinyl ring; different N-substituents on the terminal ring were introduced, a straight chain ethyl group, a branched tert. butyl and P-chlorophenyl group rather than n-butyl group of the lead compound. All four possible diastereomers of target tetrahydro-β-carboline derivatives were prepared, separated by column chromatography and the significance of these stereochemical manipulations were studied. Synthesized compounds were evaluated for their inhibitory effect versus PDE5. Seven hits were obtained with appreciable inhibitory activity versus PDE5 with IC₅₀s 0.14 - 4.99 µM.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy and Biotechnology, German University in Cairo, Egypt. nermin.salah@guc.edu.eg
Nermin S
NS
Ahmed
Bernard D
BD
Gary
Gary A
GA
Piazza
Heather N
HN
Tinsley
Stefan
S
Laufer
Ashraf H
AH
Abadi
D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D058986:Phosphodiesterase 5 Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000068581:Tadalafil
D002243:Carbolines; C558762:GR30040X compound; D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5