SCH 45752--an inhibitor of calmodulin-sensitive cyclic nucleotide phosphodiesterase activity.
A highly potent inhibitor of calmodulin-sensitive phosphodiesterase (PDE) activity was isolated from the culture broth of an unidentified fungal isolate, SCF-125. A chemically defined medium was developed for production of this compound. The PDE inhibitor was isolated from the fermentation filtrate by adsorption on a macro-reticular resin and further purified by gel filtration chromatography and reverse-phase HPLC. The major PDE inhibitor was identified as cephalochromin, a bis-naphthopyrone, by spectral data analysis. The compound, SCH 45752, inhibited calmodulin-sensitive PDE activities with IC50 values of 40-47 nM. It inhibited the activities of calmodulin-independent PDE and various protein kinases with higher IC50 values (2-40 microM). SCH 45752 does not appear to be a calmodulin antagonist. Furthermore, SCH 45752 affects smooth muscle contraction at a concentration of 30 microM; it potentiated the relaxing effect of sodium nitroprusside on carotid artery media contracted by histamine. Thus SCH 45752 is one of the most potent inhibitors of calmodulin-sensitive PDE activity known, and it is capable of exerting a pharmacological effect in at least one intact tissue model.
Hegde
V R
VR
Schering-Plough Research Institute, Kenilwooth, NJ 07033.
Miller
J R
JR
Patel
M G
MG
King
A H
AH
Puar
M S
MS
Horan
A
A
Hart
R
R
Yarborough
R
R
Gullo
V
V
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002147:Calmodulin / Q000494:pharmacology*; D002417:Cattle; D002511:Cephalosporins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D005285:Fermentation; D005658:Fungi / Q000378:metabolism*; D066298:In Vitro Techniques; D011817:Rabbits; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects
D002147:Calmodulin; D002511:Cephalosporins; C011417:cephalochromin; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases