ABSTRACT
Tertiary hydroxyl class of C-imidazole bridgehead azaheptapyridine FPT inhibitors were prepared in an attempt to block in vivo oxidation of secondary hydroxyl series. One representative compound 5a exhibited potent enzyme (IC50=1.4 nM) and cellular activities (soft agar IC50=1.3 nM) with excellent oral pharmacokinetic profiles in rats, mice, monkeys and dogs. The in vivo study in wap-ras TG mouse models showed dose dependent tumor growth inhibition and regression.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Enzyme Inhibitors/pharmacology , Neoplasms, Experimental/drug therapy , Pyridines/pharmacology , Alkyl and Aryl Transferases/metabolism , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dogs , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Haplorhini , Humans , Mice , Mice, Transgenic , Models, Molecular , Molecular Structure , Neoplasms, Experimental/pathology , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Structure-Activity Relationship , Xenograft Model Antitumor AssaysABSTRACT
In the search for a second generation HCV protease inhibitor, molecular modeling studies of the X-ray crystal structure of Boceprevir1 bound to the NS3 protein suggest that expansion into the S4 pocket could provide additional hydrophobic Van der Waals interactions. Effective replacement of the P4 tert-butyl with a cyclohexylmethyl ligand led to inhibitor 2 with improved enzyme and replicon activities. Subsequent modeling and SAR studies led to the pyridine 38 and sulfone analogues 52 and 53 with vastly improved PK parameters in monkeys, forming a new foundation for further exploration.
Subject(s)
Antiviral Agents/chemistry , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Area Under Curve , Biological Availability , Crystallography, X-Ray , Haplorhini , Models, Molecular , Proline/chemistry , Proline/pharmacokinetics , Proline/pharmacology , Protease Inhibitors/pharmacokinetics , Protease Inhibitors/pharmacology , Rats , Structure-Activity RelationshipABSTRACT
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom.
Subject(s)
Drug Discovery/methods , Farnesyltranstransferase/antagonists & inhibitors , Imidazoles/chemistry , Pyridines/chemistry , Cell Line, Tumor , Crystallography, X-Ray , Farnesyltranstransferase/metabolism , Humans , Imidazoles/metabolism , Imidazoles/pharmacology , Pyridines/metabolism , Pyridines/pharmacologyABSTRACT
Farnesyl protein transferase (FPT) inhibition is an interesting and promising approach to noncytotoxic anticancer therapy. Research in this area has resulted in several orally active compounds that are in clinical trials. Electrospray ionization (ESI) time-of-flight mass spectrometry (TOF-MS) was used for the direct detection of a 95 182 Da pentameric noncovalent complex of alpha/beta subunits of FPT containing Zn, farnesyl pyrophosphate (FPP) and SCH 66336, a compound currently undergoing phase III clinical trials as an anticancer agent. It was noted that the desalting of protein samples was an important factor in the detection of the complex. This study demonstrated that the presence of FPP in the system was necessary for the detection of the FPT-inhibitor complex. No pentameric complex was detected in the spectrum when the experiment was carried out in the absence of the FPP. An indirect approach was also applied to confirm the noncovalent binding of SCH 66336 to FPT by the use of an off-line size exclusion chromatography followed by liquid chromatography-electrospray ionization mass spectrometry (LC-ESI-MS) for the detection of the inhibitor.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Enzyme Inhibitors/pharmacology , Piperidines/pharmacology , Pyridines/pharmacology , Alkyl and Aryl Transferases/metabolism , Chromatography, Gel , Enzyme Inhibitors/metabolism , Mass Spectrometry , Molecular Weight , Piperidines/metabolism , Protein Denaturation , Pyridines/metabolism , Spectrometry, Mass, Electrospray IonizationABSTRACT
As part of a detailed study, the syntheses, biological activities, and pharmacokinetic properties of hydroxylated analogues of the previously described broad spectrum antifungal agents, Sch 51048 (1), Sch 50001 (3), and Sch 50002 (4), are described. Based on an overall superior profile, one of the alcohols, Sch 56592 (2), was selected for clinical studies.
Subject(s)
Antifungal Agents/pharmacology , Chemistry, Pharmaceutical/methods , Triazoles/chemistry , Triazoles/chemical synthesis , Triazoles/pharmacology , Alcohols , Animals , Antifungal Agents/chemistry , Aspergillosis/drug therapy , Candidiasis/drug therapy , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Haplorhini , Humans , Immunosuppressive Agents/pharmacology , Mice , Models, Chemical , Time Factors , Triazoles/pharmacokineticsABSTRACT
Hepatitis C virus (HCV) NS3, when bound to NS-4A cofactor, facilitates development of mature virons by catalyzing cleavage of a polyprotein to form functional and structural proteins of HCV. The enzyme has a shallow binding pocket at the catalytic site, making development of inhibitors difficult. We have designed, preorganized, and depeptidized macrocyclic inhibitors from P(4) to P(2)' and optimized binding to 0.1 microM. The structure of an inhibitor bound to the enzyme was also solved.
Subject(s)
Antiviral Agents/chemical synthesis , Hepacivirus/enzymology , Macrocyclic Compounds/chemical synthesis , Peptides/chemistry , Protease Inhibitors/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Binding Sites , Crystallography, X-Ray , Drug Design , Hydrogen Bonding , Macrocyclic Compounds/chemistry , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistry , Protein Binding , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistryABSTRACT
The four 2,2,5-regioisomer counterparts of SCH 51048 were synthesized and evaluated. As with the parent series, only the two cis isomers possessed any in vitro activity, and only the activity of the isomer with the R-configuration at the tetrahydrofuran 2-carbon was significant. The activity data suggests that oxygen at only one of the two possible ring positions benzylic to the difluorobenzene participates usefully in active site binding.
