CJ-13,981 and CJ-13,982, new squalene synthase inhibitors.
Two new squalene synthase (SSase) inhibitors, CJ-13,981 (I) and CJ-13,982 (II), were isolated from the fermentation broth of an unidentified fungus CL 15036. They inhibited human liver microsomal SSase with IC50s of 2.8 and 1.1 microM, respectively, but showed no inhibitory activity against human brain protein farnesyltransferase (PFTase) at 100 microM. Based on FAB-MS and NMR analyses, the structures of I and II were determined to be 3-hydroxy-3,4-dicarboxy-15-hexadecenoic acid and 3-hydroxy-3,4-dicarboxyhexadecanoic acid, respectively.
Watanabe
S
S
Exploratory Medicinal Sciences, PGRD, Nagoya Laboratories, Pfizer Pharmaceuticals Inc., Aichi, Japan. Shuzo.Watanabe@japan.pfizer.com
Hirai
H
H
Kambara
T
T
Kojima
Y
Y
Nishida
H
H
Sugiura
A
A
Yamauchi
Y
Y
Yoshikawa
N
N
Harwood
H J
HJ
Huang
L H
LH
Kojima
N
N
D019883:Alkyl and Aryl Transferases / Q000187:drug effects; D000818:Animals; D001921:Brain / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051231:Farnesyltranstransferase; D005285:Fermentation; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D019308:Palmitic Acid / Q000302:isolation & purification* / Q000494:pharmacology; D010169:Palmitic Acids; D051381:Rats; D017208:Rats, Wistar
C449025:CJ-13,981; C449024:CJ-13,982; D004791:Enzyme Inhibitors; D010169:Palmitic Acids; D019308:Palmitic Acid; D002784:Cholesterol; D019883:Alkyl and Aryl Transferases; D013186:Farnesyl-Diphosphate Farnesyltransferase; D051231:Farnesyltranstransferase