RESUMO
We describe the design, synthesis, and evaluation of novel disubstituted cyclohexanes as potent CCR2 antagonists. Exploratory SAR studies led to the cis-disubstituted derivative 22, which displayed excellent binding affinity for CCR2 (binding IC50 = 5.1 nM) and potent functional antagonism (calcium flux IC50 = 18 nM and chemotaxis IC 50 = 1 nM). Site-directed mutagenesis studies with 22 suggest the compound is binding near the key receptor residue Glu291, however, 22 is not reliant on Glu291 for its binding affinity.
Assuntos
Cicloexanos/síntese química , Receptores CCR2/antagonistas & inibidores , Ligação Competitiva , Cálcio/metabolismo , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Cicloexanos/química , Cicloexanos/farmacologia , Humanos , Técnicas In Vitro , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Modelos Moleculares , Mutagênese Sítio-Dirigida , Ensaio Radioligante , Receptores CCR2/genética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Beta-benzamido hydroxamic acids were discovered as potent TACE inhibitors. A computer model was constructed to help understanding the binding activities and guiding SAR study. SAR optimization led to the discovery of compound 30 which met all in vitro and in vivo criteria for the program and was selected for further evaluation.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Proteínas ADAM/química , Proteínas ADAM/metabolismo , Proteína ADAM17 , Administração Oral , Animais , Benzamidas/química , Benzamidas/farmacocinética , Benzamidas/farmacologia , Sítios de Ligação , Disponibilidade Biológica , Cães , Ácidos Hidroxâmicos/farmacocinética , Modelos Moleculares , Inibidores de Proteases/farmacocinética , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , SuínosRESUMO
In an effort to obtain a MMP selective and potent inhibitor of HER-2 sheddase (ADAM-10), the P1' group of a novel class of (6S,7S)-7-[(hydroxyamino)carbonyl]-6-carboxamide-5-azaspiro[2.5]octane-5-carboxylates was attenuated and the structure-activity relationships (SAR) will be discussed. In addition, it was discovered that unconventional perturbation of the P2' moiety could confer MMP selectivity, which was hypothesized to be a manifestation of the P2' group effecting global conformational changes.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Ácidos Hidroxâmicos/química , Proteínas de Membrana/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Receptor ErbB-2/antagonistas & inibidores , Proteínas ADAM/metabolismo , Proteína ADAM10 , Amidas/síntese química , Amidas/química , Amidas/farmacologia , Secretases da Proteína Precursora do Amiloide/metabolismo , Compostos Aza/síntese química , Compostos Aza/química , Compostos Aza/farmacologia , Desenho de Fármacos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Proteínas de Membrana/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Receptor ErbB-2/metabolismo , Compostos de Espiro/síntese química , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
The design, synthesis, evaluation, and identification of a novel class of (6S,7S)-N-hydroxy-6-carboxamide-5-azaspiro[2.5]octane-7-carboxamides as the first potent and selective inhibitors of human epidermal growth factor receptor-2 (HER-2) sheddase is described. Several compounds were identified that possess excellent pharmacodynamic and pharmacokinetic properties and were shown to decrease tumor size, cleaved HER-2 extracellular domain plasma levels, and potentiate the effects of the humanized anti-HER-2 monoclonal antibody (trastuzumab) in vivo in a HER-2 overexpressing cancer murine xenograft model.
Assuntos
Amidas/síntese química , Antineoplásicos/síntese química , Ácidos Hidroxâmicos/síntese química , Piperidinas/síntese química , Receptor ErbB-2/antagonistas & inibidores , Compostos de Espiro/síntese química , Administração Oral , Amidas/farmacocinética , Amidas/farmacologia , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Humanos , Ácidos Hidroxâmicos/farmacocinética , Ácidos Hidroxâmicos/farmacologia , Camundongos , Conformação Molecular , Piperidinas/química , Piperidinas/farmacologia , Compostos de Espiro/química , Compostos de Espiro/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Transplante Heterólogo , TrastuzumabRESUMO
Recently, an X-ray co-crystal structure of our hydroxamate inhibitor IK682 and TACE [Niu, X.; Umland, S.; Ingram, R.; Beyer, B. M.; Liu, Y.-H.; Sun, J.; Lundell, D.; Orth, P. Arch. Biochem. Biophys. 2006, 451, 43-50] was published that explicitly shows the orientation of the hydroxamate and the TACE-selective 4-[(2-methyl-4-quinolinyl)methoxy]phenyl P1' group in the S1' and S3' sites. The preceding paper described a novel series of potent and TACE-selective hydantoins and we previously described pyrimidinetrione (barbiturate) inhibitors of TACE, both of which contain the same P1' group as IK682. Using this TACE-selective P1' group as an anchor, stereochemical and conformational constraints in the inhibitors, and restrictions to the active site Zn coordination geometry, we developed a highly plausible and predictive pharmacophore model that rationalizes the observed TACE activity of all three inhibitors.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Modelos Moleculares , Proteínas ADAM/química , Proteína ADAM17 , Sítios de Ligação , Humanos , Hidantoínas/química , Hidantoínas/farmacologia , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Lactamas/química , Lactamas/farmacologia , Conformação Molecular , Pirimidinonas/química , Pirimidinonas/farmacologia , Relação Estrutura-Atividade , Zinco/químicaRESUMO
Crystal structures of protein-tyrosine phosphatase 1B in complex with compounds bearing a novel isothiazolidinone (IZD) heterocyclic phosphonate mimetic reveal that the heterocycle is highly complementary to the catalytic pocket of the protein. The heterocycle participates in an extensive network of hydrogen bonds with the backbone of the phosphate-binding loop, Phe(182) of the flap, and the side chain of Arg(221). When substituted with a phenol, the small inhibitor induces the closed conformation of the protein and displaces all waters in the catalytic pocket. Saturated IZD-containing peptides are more potent inhibitors than unsaturated analogs because the IZD heterocycle and phenyl ring directly attached to it bind in a nearly orthogonal orientation with respect to each other, a conformation that is close to the energy minimum of the saturated IZD-phenyl moiety. These results explain why the heterocycle is a potent phosphonate mimetic and an ideal starting point for designing small nonpeptidic inhibitors.
Assuntos
Mimetismo Molecular , Organofosfonatos/farmacologia , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Tiazóis/farmacologia , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Escherichia coli/genética , Humanos , Ligação de Hidrogênio , Hidrólise , Concentração Inibidora 50 , Cinética , Modelos Moleculares , Estrutura Molecular , Conformação Proteica/efeitos dos fármacos , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/análise , Proteínas Tirosina Fosfatases/isolamento & purificação , Relação Estrutura-Atividade , Especificidade por Substrato , Água/químicaRESUMO
The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure-activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation.
Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Tiazóis/química , Tiazóis/farmacologia , Escherichia coli , Humanos , Modelos Moleculares , Estrutura Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Proteína Tirosina Fosfatase não Receptora Tipo 6 , Relação Estrutura-AtividadeRESUMO
Potent nonpeptidic benzimidazole sulfonamide inhibitors of protein tyrosine phosphatase 1B (PTP1B) were derived from the optimization of a tripeptide containing the novel (S)-isothiazolidinone ((S)-IZD) phosphotyrosine (pTyr) mimetic. An X-ray cocrystal structure of inhibitor 46/PTP1B at 1.8 A resolution demonstrated that the benzimidazole sulfonamides form a bidentate H bond to Asp48 as designed, although the aryl group of the sulfonamide unexpectedly interacts intramolecularly in a pi-stacking manner with the benzimidazole. The ortho substitution to the (S)-IZD on the aryl ring afforded low nanomolar enzyme inhibitors of PTP1B that also displayed low caco-2 permeability and cellular activity in an insulin receptor (IR) phosphorylation assay and an Akt phosphorylation assay. The design, synthesis, and SAR of this novel series of benzimidazole sulfonamide containing (S)-IZD inhibitors of PTP1B are presented herein.
Assuntos
Benzimidazóis/síntese química , Oligopeptídeos/química , Fosfotirosina/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Sulfonamidas/síntese química , Tiazóis/síntese química , Benzimidazóis/química , Benzimidazóis/farmacologia , Linhagem Celular , Cristalografia por Raios X , Humanos , Modelos Moleculares , Mimetismo Molecular , Estrutura Molecular , Fosforilação , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Proteínas Tirosina Fosfatases/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor de Insulina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologia , Tiazóis/química , Tiazóis/farmacologiaRESUMO
Structure-based design led to the discovery of novel (S)-isothiazolidinone ((S)-IZD) heterocyclic phosphotyrosine (pTyr) mimetics that when incorporated into dipeptides are exceptionally potent, competitive, and reversible inhibitors of protein tyrosine phosphatase 1B (PTP1B). The crystal structure of PTP1B in complex with our most potent inhibitor 12 revealed that the (S)-IZD heterocycle interacts extensively with the phosphate binding loop precisely as designed in silico. Our data provide strong evidence that the (S)-IZD is the most potent pTyr mimetic reported to date.
Assuntos
Dipeptídeos/síntese química , Fosfotirosina/química , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/química , Tiazóis/síntese química , Cristalografia por Raios X , Dipeptídeos/química , Desenho de Fármacos , Modelos Moleculares , Mimetismo Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Relação Quantitativa Estrutura-Atividade , Estereoisomerismo , Tiazóis/químicaRESUMO
The design and synthesis of tetrapeptide-based alpha-ketoamides containing prime side acid isosteres HCV NS3 protease inhibitors are described. Tetrazole, sulfonic acid, and N-sulfonylcarboxamids were demonstrated to be efficient carboxylic acid replacements. Further optimization yielded a series of potent HCV NS3 protease inhibitors with IC(50) of 0.020-0.060 microM.
Assuntos
Amidas/síntese química , Glicina/análogos & derivados , Hepacivirus/enzimologia , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/química , Amidas/farmacologia , Sítios de Ligação , Ácidos Carboxílicos/química , Glicina/síntese química , Glicina/farmacologia , Concentração Inibidora 50 , Inibidores de Proteases/farmacologia , Relação Estrutura-Atividade , Ácidos Sulfônicos/química , Tetrazóis/químicaRESUMO
New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered with a pyrimidine-2,4,6-trione in place of the commonly used hydroxamic acid. These non-hydroxamate TACE inhibitors were developed by incorporating a 4-(2-methyl-4-quinolinylmethoxy)phenyl group, an optimized TACE selective P1' group. Several leads were identified with IC50 values around 100 nM in a porcine TACE assay and selective over MMP-1, -2, -9, -13, and aggrecanase.
Assuntos
Ácidos Hidroxâmicos/química , Inibidores de Metaloproteinases de Matriz , Metaloendopeptidases/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Pirimidinas/farmacologia , Proteínas ADAM , Proteína ADAM17 , Animais , Endopeptidases/química , Estrutura Molecular , Inibidores de Proteases/síntese química , Inibidores de Proteases/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , SuínosRESUMO
The paradigm for matrix metalloprotease inhibition combines active site tailoring and catalytic zinc ligation. But, selectivity has been difficult. Now, Engel et al. present novel compounds, completely selective for MMP-13, with a unique binding mode.
Assuntos
Inibidores de Metaloproteinases de Matriz , Metaloproteinases da Matriz/química , Catálise , Domínio Catalítico , Inibidores Enzimáticos , Estrutura Secundária de ProteínaRESUMO
In this communication we describe the design, synthesis, and evaluation of novel sultam hydroxamates 4 as MMP-2, -9, and -13 inhibitors. Compound 26 was found to be an active inhibitor (MMP-2 IC(50) = 1 nM) with 1000-fold selectivity over MMP-1 and good oral bioavailability (F = 43%) in mouse. An X-ray crystal structure of 26 in MMP-13 confirms the key hydrogen bonds and prime side binding in the active site.
Assuntos
Ácidos Hidroxâmicos/síntese química , Inibidores de Metaloproteinases de Matriz , Sulfonamidas/síntese química , Administração Oral , Animais , Disponibilidade Biológica , Cristalografia por Raios X , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Metaloproteinase 13 da Matriz , Camundongos , Modelos Moleculares , Relação Estrutura-Atividade , Sulfonamidas/química , Sulfonamidas/farmacologiaRESUMO
New inhibitors of tumor necrosis factor-alpha converting enzyme (TACE) were discovered using an N-hydroxy-2-(2-oxo-3-pyrrolidinyl)acetamide scaffold. The series was found to be potent in a porcine TACE (pTACE) assay with IC(50)s typically below 5 nM. For most compounds, selectivity for pTACE relative to MMP-1,-2, and -9 is at least 300-fold. Compound 2o was potent in inhibition of TNFalpha production in a human whole blood assay (WBA) with an IC(50) of 0.42 micro M.
Assuntos
Acetamidas/química , Acetamidas/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Metaloendopeptidases/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Acetamidas/síntese química , Animais , Humanos , Concentração Inibidora 50 , Lactamas/química , Lactamas/farmacologia , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Relação Estrutura-Atividade , Suínos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/biossínteseRESUMO
The MMP-11 proteinase, also known as stromelysin-3, probably plays an important role in human cancer because MMP-11 is frequently overexpressed in human tumors and MMP-11 levels affect tumorogenesis in mice. Unlike other MMPs, however, human MMP-11 does not cleave extracellular matrix proteins, such as collagen, laminin, fibronectin, and elastin. To help identify physiologic MMP-11 substrates, a phage display library was used to find peptide substrates for MMP-11. One class of peptides containing 26 members had the consensus sequence A(A/Q)(N/A) downward arrow (L/Y)(T/V/M/R)(R/K), where downward arrow denotes the cleavage site. This consensus sequence was similar to that for other MMPs, which also cleave peptides containing Ala in position 3, Ala in position 1, and Leu/Tyr in position 1', but differed from most other MMP substrates in that proline was rarely found in position 3 and Asn was frequently found in position 1. A second class of peptides containing four members had the consensus sequence G(G/A)E downward arrow LR. Although other MMPs also cleave peptides with these residues, other MMPs prefer proline at position 3 in this sequence. In vitro assays with MMP-11 and representative peptides from both classes yielded modest kcat/Km values relative to values found for other MMPs with their preferred peptide substrates. These reactions also showed that peptides with proline in position 3 were poor substrates for MMP-11. A structural basis for the lower kcat/Km values of human MMP-11, relative to other MMPs, and poor cleavage of position 3 proline substrates by MMP-11 is provided. Taken together, these findings explain why MMP-11 does not cleave most other MMP substrates and predict that MMP-11 has unique substrates that may contribute to human cancer.
Assuntos
Metaloendopeptidases/química , Biblioteca de Peptídeos , Sítios de Ligação , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Matriz Extracelular/metabolismo , Vetores Genéticos , Humanos , Cinética , Metaloproteinase 11 da Matriz , Metaloproteinases da Matriz Associadas à Membrana , Metaloendopeptidases/metabolismo , Metaloendopeptidases/fisiologia , Modelos Moleculares , Neoplasias/metabolismo , Peptídeos/química , Prolina/química , Ligação Proteica , Estrutura Terciária de Proteína , Especificidade por SubstratoRESUMO
Elevated levels of tumor necrosis factor-alpha (TNF-alpha) have been associated with several inflammatory diseases, and therefore, strategies for its suppression have become important targets in drug discovery. Our efforts to suppress TNF-alpha have centered on the inhibition of TNF-alpha converting enzyme (TACE) through the use of hydroxamate inhibitors. Starting from broad-spectrum matrix metalloproteinase (MMP) inhibitors, we have designed and synthesized novel benzothiadiazepines as potent and selective TACE inhibitors. The benzothiadiazepines were synthesized with variation in P1 and P1' in order to effect potency and selectivity. The inhibitors were evaluated versus porcine TACE (pTACE), and the initial selectivity was assessed with counterscreens of MMP-1, -2, and -9. Several potent and selective inhibitors were discovered with compound 41 being the most active against pTACE (K(i) = 5 nM) while still maintaining good selectivity versus the MMP's (at least 75-fold). Most compounds were assessed in the human peripheral blood mononuclear cell assay (PBMC) and the human whole blood assay (WBA) to determine their ability to suppress TNF-alpha. Compound 32 was the most potent compound in the PBMC assay (IC(50) = 0.35 microM), while compound 62 was the most active in the WBA (IC(50) = 1.4 microM).
Assuntos
Benzodiazepinonas/síntese química , Inibidores Enzimáticos/síntese química , Ácidos Hidroxâmicos/síntese química , Metaloendopeptidases/antagonistas & inibidores , Tiazepinas/síntese química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Proteínas ADAM , Proteína ADAM17 , Animais , Benzodiazepinonas/química , Benzodiazepinonas/farmacologia , Proteínas Sanguíneas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz , Modelos Moleculares , Ligação Proteica , Relação Estrutura-Atividade , Suínos , Tiazepinas/química , Tiazepinas/farmacologia , Fator de Necrose Tumoral alfa/biossínteseRESUMO
Inhibition of tumor necrosis factor-alpha converting enzyme (TACE) is a widespread objective in the search for disease modifying agents to combat rheumatoid arthritis and other autoimmune diseases. Until recently, most of the inhibitors in the literature have shown concomitant activity against the related matrix metalloproteinases (MMPs), producing undesired side effects. Here we describe the successful search for a TACE selectivity mechanism. We built a homology model based on the crystal structure of the related snake venom protein atrolysin. Comparison of the model with crystal structures of MMPs suggested a uniquely shaped S1' pocket that might be exploited for selectivity. A novel gamma-lactam scaffold was used to explore the activity profile of P1' sidechains, resulting in highly selective compounds consistent with this hypothesis. Transferability of the hypothesis was then demonstrated with five other distinct scaffolds.
Assuntos
Metaloendopeptidases/antagonistas & inibidores , Metaloendopeptidases/química , Modelos Químicos , Modelos Moleculares , Proteínas ADAM , Proteína ADAM17 , Sequência de Aminoácidos , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Inibidores Enzimáticos/química , Lactamas/química , Metaloproteinases da Matriz/química , Dados de Sequência Molecular , Estrutura Molecular , Homologia de Sequência de Aminoácidos , Venenos de Serpentes/química , Fator de Necrose Tumoral alfa/químicaRESUMO
Anti-succinate hydroxamates with cyclic P1 motifs were synthesized as aggrecanase inhibitors. The N-methanesulfonyl piperidine 23 and the N-trifluoroacetyl azetidine 26 were the most potent aggrecanase inhibitors both having an IC(50)=3nM while maintaining >100-fold selectivity over MMP-1, -2, and -9. The cyclic moieties were also capable of altering in vivo metabolism, hence delivering low clearance compounds in both rat and dog studies as shown for compound 14.
Assuntos
Endopeptidases/metabolismo , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Animais , Bovinos , Cães , Meia-Vida , Ácidos Hidroxâmicos/farmacocinética , Indicadores e Reagentes , Isoenzimas/antagonistas & inibidores , Inibidores de Proteases/farmacocinética , RatosRESUMO
Using a tetrapeptide-based alpha-ketoamide template, various amines and amino acids were incorporated to explore the prime side of the HCV NS3 protease catalytic site. Glycine carboxylic acid was found to be the most effective prime group. Further optimization yielded an inhibitor with IC(50) of 0.060 microM.
Assuntos
Amidas/síntese química , Amidas/farmacologia , Glicina/síntese química , Glicina/farmacologia , Hepacivirus/enzimologia , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/metabolismo , Aminas/química , Aminoácidos/química , Sítios de Ligação , Glicina/análogos & derivados , Relação Estrutura-AtividadeRESUMO
Starting from a hexapeptide boronic acid lead, 3-amino bicyclic pyrazinones as novel beta-sheet dipeptide mimetics have been designed and synthesized. Side-chain manipulation of this scaffold generated a series of potent, nonpeptidic inhibitors of HCV NS3 protease.