HCV NS5b RNA-dependent RNA polymerase inhibitors: from alpha,gamma-diketoacids to 4,5-dihydroxypyrimidine- or 3-methyl-5-hydroxypyrimidinonecarboxylic acids. Design and synthesis.
A new class of the HCV NS5b RNA-dependent RNA polymerase inhibitors, the dihyroxypyrimidinecarboxylic acid derivative, was designed from a diketoacid and meconic acid derivative discovered by screening. Mechanism of action and essential moieties required for activity were identified. The corresponding N-methylpyrimidinone was also prepared; both classes are novel, reversible, and selective inhibitors of the HCV NS5b polymerase with improved druglike characteristics.
Summa
Vincenzo
V
Departments of Medicinal Chemistry and Biochemistry IRBM-MRL Rome, Via Pontina, Km 30.600, 00040 Pomezia (Rome), Italy. Vincenzo_summa@merck.com
Petrocchi
Alessia
A
Matassa
Victor G
VG
Taliani
Marina
M
Laufer
Ralph
R
De Francesco
Raffaele
R
Altamura
Sergio
S
Pace
Paola
P
D000818:Animals; D001665:Binding Sites; D015195:Drug Design; D016174:Hepacivirus / Q000201:enzymology; D066298:In Vitro Techniques; D007536:Isomerism; D007651:Keto Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000378:metabolism*
D007651:Keto Acids; D011743:Pyrimidines; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase