ABSTRACT
HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.
Subject(s)
HIV Integrase Inhibitors/chemistry , HIV Integrase Inhibitors/pharmacology , HIV Integrase/metabolism , HIV-1/enzymology , Pyridones/chemistry , Pyridones/pharmacology , Animals , Dogs , HIV Infections/drug therapy , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , Humans , Molecular Docking Simulation , Pyridones/pharmacokineticsABSTRACT
The search for new molecular constructs that resemble the critical two-metal binding pharmacophore required for HIV integrase strand transfer inhibition represents a vibrant area of research within drug discovery. Here we present the discovery of a new class of HIV integrase strand transfer inhibitors based on the 2-pyridinone core of MK-0536. These efforts led to the identification of two lead compounds with excellent antiviral activity and preclinical pharmacokinetic profiles to support a once-daily human dose prediction. Dose escalating PK studies in dog revealed significant issues with limited oral absorption and required an innovative prodrug strategy to enhance the high-dose plasma exposures of the parent molecules.
Subject(s)
HIV Integrase Inhibitors/chemical synthesis , HIV Integrase Inhibitors/pharmacology , Pyridones/chemical synthesis , Pyridones/pharmacology , Animals , Area Under Curve , Dogs , Dose-Response Relationship, Drug , Drug Design , HIV Integrase/drug effects , HIV Integrase/metabolism , HIV Integrase Inhibitors/pharmacokinetics , HIV-1/drug effects , HIV-1/enzymology , HIV-1/genetics , Humans , Models, Molecular , Prodrugs , Pyridones/pharmacokinetics , RatsABSTRACT
We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Chemistry, Pharmaceutical/methods , Pyrrolidines/pharmacology , Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid Endopeptidases/antagonists & inhibitors , Crystallization , Crystallography, X-Ray/methods , Drug Design , Enzyme Inhibitors/pharmacology , Inhibitory Concentration 50 , Ligands , Models, Chemical , Protein Binding , Structure-Activity RelationshipABSTRACT
A small molecule inhibitor of beta-secretase with a unique binding mode has been developed. Crystallographic determination of the enzyme-inhibitor complex shows the catalytic aspartate residues in the active site are not engaged in inhibitor binding. This unprecedented binding mode in the field of aspartyl protease inhibition is described.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aspartic Acid , Enzyme Inhibitors/pharmacokinetics , Amyloid Precursor Protein Secretases/metabolism , Aspartic Acid Endopeptidases/antagonists & inhibitors , Aspartic Acid Endopeptidases/metabolism , Catalytic Domain , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Protein BindingABSTRACT
A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.
Subject(s)
Amides/chemistry , Endopeptidases/metabolism , Protease Inhibitors/chemical synthesis , Amyloid Precursor Protein Secretases , Binding Sites , Immunoassay , Peptides/chemistry , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
We have synthesized and evaluated a series of conformationally biased P3 amide replacements based on an isophthalamide lead structure. The studies resulted in the identification of the beta-secretase inhibitor 7m which has an in vitro IC(50)=35 nM. The synthesis and biological activities of these compounds are described.
Subject(s)
Amides/chemistry , Endopeptidases/metabolism , Protease Inhibitors/chemical synthesis , Amides/pharmacology , Amyloid Precursor Protein Secretases , Drug Design , Inhibitory Concentration 50 , Models, Molecular , Phthalic Acids/chemistry , Protease Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
We describe the development of cell-permeable beta-secretase inhibitors that demonstratively inhibit the production of the secreted amino terminal fragment of an artificial amyloid precursor protein in cell culture. In addition to potent inhibition in a cell-based assay (IC50 < 100 nM), these inhibitors display impressive selectivity against other biologically relevant aspartyl proteases.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Ethylamines/chemical synthesis , Sulfonamides/chemical synthesis , Amyloid Precursor Protein Secretases , Aspartic Acid Endopeptidases/chemistry , Binding Sites , Cell Line , Cell Membrane Permeability , Crystallography, X-Ray , Drug Design , Ethylamines/chemistry , Ethylamines/pharmacology , Humans , Models, Molecular , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
