ABSTRACT
HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.
Subject(s)
Antiviral Agents/therapeutic use , Drug Discovery , Lactams/therapeutic use , Protease Inhibitors/therapeutic use , Sulfonamides/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Crystallography, X-Ray , Cyclopropanes , Dogs , Isoindoles , Lactams/chemistry , Lactams/pharmacology , Lactams, Macrocyclic , Macaca fascicularis , Molecular Structure , Proline/analogs & derivatives , Protease Inhibitors/pharmacology , Rats , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K(i) = 58 microM via a potency enhancement of >70 000-fold to an analogue with an activity of K(i) = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure-activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180 degrees variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.
Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Influenza A virus/enzymology , Neuraminidase/antagonists & inhibitors , Neuraminidase/chemistry , Amines/chemistry , Animals , Binding Sites , Birds , Combinatorial Chemistry Techniques/methods , Crystallization , Crystallography, X-Ray , Cyclopentanes/chemical synthesis , Enzyme Inhibitors/chemistry , Esters , Models, Molecular , Nanotechnology/methods , Neuraminidase/isolation & purification , Pyrrolidines/chemical synthesis , Stereoisomerism , Structure-Activity RelationshipABSTRACT
[reaction: see text] The preparation and synthetic applications of a novel resin-bound isonitrile are described. The resin is an example of a novel convertible isonitrile that can be utilized in the Ugi multicomponent reaction. Base-activation of the resin-bound Ugi product results in cleavage via formation of a N-acyloxazolidone that is then trapped as a carboxylic acid ester. This resin and the methodology described are suitable for synthesizing diversity libraries of 2,5-diketopiperazines and 1,4-benzodiazepine-2,5-diones.
