Synthesis and biological activities of novel beta-carbolines as PDE5 inhibitors.
A series of N(2)-furoyl and N(2)pyrimidinyl beta-carbolines was discovered to possess potent inhibitory activity against PDE5. During the synthesis we developed a tandem resin quenching protocol, which allowed us to synthesize large number of target compounds in a rapid fashion. Representative compounds exhibit superior selectivity to sildenafil versus other isozymes of PDEs, and demonstrated in vivo efficacy in increasing introcavernosal pressure in dogs.
Sui
Zhihua
Z
Johnson & Johnson Pharmaceutical Research & Development L.L.C., 1000 Route 202, Raritan, NJ 08869, USA. zsui@prius.jnj.com
Guan
Jihua
J
Macielag
Mark J
MJ
Jiang
Weiqin
W
Qiu
Yuhong
Y
Kraft
Patricia
P
Bhattacharjee
Sheela
S
John
T Matthew
TM
Craig
Elizabeth
E
Haynes-Johnson
Donna
D
Clancy
Joanna
J
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002243:Carbolines / Q000138:chemical synthesis* / Q000494:pharmacology*; D020650:Combinatorial Chemistry Techniques / Q000379:methods; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D007172:Erectile Dysfunction / Q000188:drug therapy; D006801:Humans; D007527:Isoenzymes; D008297:Male; D010413:Penis / Q000187:drug effects; D010879:Piperazines; D011687:Purines; D000068677:Sildenafil Citrate; D012995:Solubility; D013329:Structure-Activity Relationship; D013450:Sulfones
D002243:Carbolines; D007527:Isoenzymes; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human