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1.
J Med Chem ; 54(9): 3368-85, 2011 May 12.
Article in English | MEDLINE | ID: mdl-21438541

ABSTRACT

A novel class of heat shock protein 90 (Hsp90) inhibitors was discovered by high-throughput screening and was subsequently optimized using a combination of structure-based design, parallel synthesis, and the application of medicinal chemistry principles. Through this process, the biochemical and cell-based potency of the original HTS lead were substantially improved along with the corresponding metabolic stability properties. These efforts culminated with the identification of a development candidate (compound 42) which displayed desired PK/PD relationships, significant efficacy in a melanoma A2058 xenograft tumor model, and attractive DMPK profiles.


Subject(s)
Antineoplastic Agents/chemical synthesis , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Pyrazoles/chemical synthesis , Pyrimidines/chemical synthesis , Administration, Oral , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Binding, Competitive , Biological Availability , Blood Proteins/metabolism , Cell Line, Tumor , Cell Membrane Permeability , Drug Screening Assays, Antitumor , Drug Stability , Female , Humans , Hydrophobic and Hydrophilic Interactions , In Vitro Techniques , Male , Melanoma/drug therapy , Melanoma/pathology , Mice , Mice, Nude , Microsomes, Liver/metabolism , Models, Molecular , Neoplasm Transplantation , Protein Binding , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Structure-Activity Relationship , Transplantation, Heterologous
2.
J Med Chem ; 46(21): 4572-85, 2003 Oct 09.
Article in English | MEDLINE | ID: mdl-14521419

ABSTRACT

The optimization of the pharmacokinetic performance of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors following oral administration to either beagle dogs or CM-monkeys is described. The molecules described in this work are composed of a 2-pyridone-containing peptidomimetic binding determinant and an alpha,beta-unsaturated ester Michael acceptor moiety which forms an irreversible covalent adduct with the active site cysteine residue of the 3C enzyme. Modification of the ester contained within these compounds is detailed along with alteration of the P(2) substituent present in the peptidomimetic portion of the inhibitors. The pharmacokinetics of several inhibitors in both dogs and monkeys are described (7 h plasma concentrations after oral administration) along with their human plasma stabilities, stabilities in incubations with human, dog, and monkey microsomes and hepatocytes, Caco-2 permeabilities, and aqueous solubilities. Compounds containing an alpha,beta-unsaturated ethyl ester fragment and either an ethyl or propargyl P(2) moiety displayed the most promising combination of 3C enzyme inhibition (k(obs)/[I] 170 000-223 000 M(-1) s(-1)), antiviral activity (EC(50) = 0.047-0.058 microM, mean vs seven HRV serotypes), and pharmacokinetics following oral administration (7 h dog plasma levels = 0.248-0.682 microM; 7 h CM-monkey plasma levels = 0.057-0.896 microM).


Subject(s)
Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacology , Cysteine Endopeptidases/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Rhinovirus/enzymology , Viral Proteins/metabolism , 3C Viral Proteases , Animals , Antiviral Agents/pharmacokinetics , Biological Availability , Blood Proteins/metabolism , Caco-2 Cells , Dogs , Drug Design , Half-Life , Hepatocytes/metabolism , Humans , In Vitro Techniques , Indicators and Reagents , Macaca fascicularis , Magnetic Resonance Spectroscopy , Male , Microsomes, Liver/metabolism , Protease Inhibitors/pharmacokinetics , Protein Binding , Rhinovirus/drug effects , Solubility , Structure-Activity Relationship
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