Inhibitors of the hepatitis C virus NS3 protease with basic amine functionality at the P3-amino acid N-terminus: Discovery and optimization of a new series of P2-P4 macrocycles

Journal of Medicinal Chemistry

Volumn 52, Issue 15, 2009, Pages 4820-4837

  Harper, Steven ^a   Ferrara, Marco ^a   Crescenzi, Benedetta ^a   Pompei, Marco ^a   Palumbi, Maria Cecilia ^a   DiMuzio, Jillian M ^a,b   Donghi, Monica ^a   Fiore, Fabrizio ^a   Koch, Uwe ^a   Liverton, Nigel J ^a,b   Pesci, Silvia ^a   Petrocchi, Alessia ^a   Rowley, Michael ^a   Summa, Vincenzo ^a   Gardelli, Cristina ^a  

^a IRBM   (Italy)

^b MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

7 CYCLOHEXYL 4 [[1 [(CYCLOPROPYLSULFONYL)CARBAMOYL] 2 ETHENYLCYCLOPROPYL]CARBAMOYL] 23 METHOXY 6 OXO 3,4,6,7,8,9,10,11,12,13 DECAHYDRO 2H 16,18 ETHENO 2,5 METHANOPYRIDO[3,2 R][1,5,8]OXADIAZACYCLONONADECIN 8 IUM TRIFLUOROACETATE; ACETIC ACID DERIVATIVE; AMINE; AMINO ACID; ANTIVIRUS AGENT; BENZENE DERIVATIVE; CILUPREVIR; CYCLOPROPANE DERIVATIVE; FLUORINE DERIVATIVE; MACROCYCLIC COMPOUND; NONSTRUCTURAL PROTEIN 3; PROTEINASE INHIBITOR; SULFONE DERIVATIVE; TRIPEPTIDE; UNCLASSIFIED DRUG;

AMINO TERMINAL SEQUENCE; ANIMAL EXPERIMENT; ANTIVIRAL ACTIVITY; AREA UNDER THE CURVE; ARTICLE; DOG; DRUG BIOAVAILABILITY; DRUG BLOOD LEVEL; DRUG CLEARANCE; DRUG HALF LIFE; DRUG LIVER LEVEL; DRUG POTENCY; HEPATITIS C VIRUS; HYDROGEN BOND; MALE; NONHUMAN; RAT; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

AMINES; ANIMALS; ANTIVIRAL AGENTS; DOGS; DRUG DISCOVERY; MALE; RATS; RATS, SPRAGUE-DAWLEY; STRUCTURE-ACTIVITY RELATIONSHIP; VIRAL NONSTRUCTURAL PROTEINS;

EID: 68549135158     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900372w     Document Type: Article

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31. Occasional reports of tripeptide-like inhibitors of the HCV NS3 protease in which the P3-N atom is uncapped (and/or is basic) have appeared in the patent literature, e.g., WO2005/051410. During the preparation of this manuscript two relevant patent applications appeared: WO2008/070733 reports a series of P1-P3 macrocyclic inhibitors containing a basic P3-N atom; WO2008/060927 reports a series of acyclic tripeptide analogues that feature aromatic or heteroaromatic P3-capping groups.
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40. max values for all compounds reported are below 4 h and are typically in the 0.5-1 h time range.
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