Quinolines as extremely potent and selective PDE5 inhibitors as potential agents for treatment of erectile dysfunction.
In a continuing effort to discover novel chemotypes as potent and selective PDE5 inhibitors for the treatment of male erectile dysfunction (ED), we have found that 4-benzylaminoquinoline derivatives are very potent and selective PDE5 inhibitors. Some compounds in this series had PDE5 IC(50)'s as low as 50 pM. While an electron withdrawing group at the C6-position of the quinoline substantially improved PDE5 potency, an ethyl group at the C8-position not only improved the PDE5 potency but also the isozyme selectivity. Substitutents at the C3-position can incorporate a variety of different groups. The synthesis and primary structure-activity relationship of this new series of potent PDE5 inhibitors are described.
Department of Discovery Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 5400, Princeton, NJ 08543-5400, USA. ybi@lexpharma.com
Yingzhi
Y
Bi
Patrick
P
Stoy
Leonard
L
Adam
Bin
B
He
John
J
Krupinski
Diane
D
Normandin
Ron
R
Pongrac
Laurie
L
Seliger
Andrew
A
Watson
John E
JE
Macor
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human