Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity.
Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).
Ahn
H S
HS
Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
Bercovici
A
A
Boykow
G
G
Bronnenkant
A
A
Chackalamannil
S
S
Chow
J
J
Cleven
R
R
Cook
J
J
Czarniecki
M
M
Domalski
C
C
Fawzi
A
A
Green
M
M
Gündes
A
A
Ho
G
G
Laudicina
M
M
Lindo
N
N
Ma
K
K
Manna
M
M
McKittrick
B
B
Mirzai
B
B
Nechuta
T
T
Neustadt
B
B
Puchalski
C
C
Pula
K
K
Zhang
H
H
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects*; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010726:Phosphodiesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases; D011758:Pyrroles; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship
D000959:Antihypertensive Agents; D007202:Indicators and Reagents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011758:Pyrroles; D006147:Guanine; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054677:Cyclic Nucleotide Phosphodiesterases, Type 1; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517384:Pde5a protein, rat