ABSTRACT
The discovery of potent, bioavailable small molecule inhibitors of p53-HDM2 PPI led us to investigate subsequent modifications to address a CYP3A4 time-dependent inhibition liability. On the basis of the crystal structure of HDM2 in complex with 2, further functionalization of the solvent exposed area of the molecule that binds to Phe19 pocket were investigated as a strategy to modulate the molecule liphophilicity. Introduction of 2-oxo-nicotinic amide at Phe19 proved a viable strategy in obtaining inhibitors exempt from CYP3A4 time-dependent inhibition liability.
Subject(s)
Cytochrome P-450 CYP3A/metabolism , Phenylalanine/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Tumor Suppressor Protein p53/antagonists & inhibitors , Dose-Response Relationship, Drug , Humans , Molecular Structure , Phenylalanine/chemistry , Protein Binding/drug effects , Proto-Oncogene Proteins c-mdm2/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolismABSTRACT
A new subseries of substituted piperidines as p53-HDM2 inhibitors exemplified by 21 has been developed from the initial lead 1. Research focused on optimization of a crucial HDM2 Trp23-ligand interaction led to the identification of 2-(trifluoromethyl)thiophene as the preferred moiety. Further investigation of the Leu26 pocket resulted in potent, novel substituted piperidine inhibitors of the HDM2-p53 interaction that demonstrated tumor regression in several human cancer xenograft models in mice. The structure of HDM2 in complex with inhibitors 3, 10, and 21 is described.
ABSTRACT
The discovery of 3,3-disubstituted piperidine 1 as novel p53-HDM2 inhibitors prompted us to implement subsequent SAR follow up directed towards piperidine core modifications. Conformational restrictions and further functionalization of the piperidine core were investigated as a strategy to gain additional interactions with HDM2. Substitutions at positions 4, 5 and 6 of the piperidine ring were explored. Although some substitutions were tolerated, no significant improvement in potency was observed compared to 1. Incorporation of an allyl side chain at position 2 provided a drastic improvement in binding potency.
Subject(s)
Piperidines/chemical synthesis , Piperidines/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Tumor Suppressor Protein p53/antagonists & inhibitors , Biological Assay , Cell Proliferation/drug effects , Humans , Inhibitory Concentration 50 , Molecular Structure , Piperidines/chemistry , Protein Binding/drug effects , Proto-Oncogene Proteins c-mdm2/metabolism , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolismABSTRACT
Hepatitis C (HCV) infection is a global health crisis leading to chronic liver disease. In our efforts towards a second generation HCV NS3 serine protease inhibitor with improved profile, we have undertaken SAR studies in various regions of Boceprevir including P2. Herein, we report the synthesis and structure-activity relationship studies of inhibitors with (S)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylic acid 2 as P2 substituent replacing the (1R,2S,5S)-6,6-dimethyl 3-azabicyclo[3.1.0]hexane-2-carboxylic acid. The systematic investigation led to the discovery of highly potent inhibitor 25 (K(i)( *)=7nM, EC(90)=30nM) with improved rat exposure of 2.56microM h.
Subject(s)
Antiviral Agents/chemistry , Proline/analogs & derivatives , Protease Inhibitors/chemistry , Quinolizines/chemistry , Sulfur Compounds/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Binding Sites , Computer Simulation , Humans , Proline/chemical synthesis , Proline/chemistry , Proline/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Hepatitis is a disease characterized by inflammation of the liver, usually producing swelling and, in many cases, permanent damage to liver tissues. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically 3% of the world's population. Boceprevir, SCH 503034, (1) our first generation HCV inhibitor, has already established proof-of- concept and is currently in late stage (phase III) clinical trials. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket by introducing a new sulfonamide moiety and optimization of the P1/P(1)' capping led to the discovery of a novel series of inhibitors of the HCV NS3 serine protease. Optimization of the P(1) residue significantly improved potency and selectivity. The combination of optimal moieties led to the discovery of compound 47 which, in addition to being a potent inhibitor of HCV subgenomic RNA replication, was also found to have good PK profile in rat, dog and monkey.
Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Serine Proteinase Inhibitors/chemistry , Sulfonamides/chemistry , Urea/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Binding Sites , Computer Simulation , Dogs , Drug Evaluation, Preclinical , Escherichia coli Proteins , Haplorhini , Humans , Membrane Proteins , Models, Molecular , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/pharmacokinetics , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokinetics , Urea/chemical synthesis , Urea/chemistry , Urea/pharmacokinetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A highly efficient and practical route to 3,4-isopropylidene proline I, starting from (+)-3-carene, was developed. The three continuous stereocenters were constructed using the inherent chirality of the starting natural product 2. The overall yield for the 12-step synthesis is 34%. The optimized sequence leading to 1 has been successfully applied on a multigram scale, thereby establishing the practicality of this route.
Subject(s)
Allyl Compounds/chemical synthesis , Monoterpenes/chemistry , Proline/analogs & derivatives , Proline/chemical synthesis , Allyl Compounds/chemistry , Bicyclic Monoterpenes , Catalysis , Chromatography, Gel , Cyclization , Molecular Sequence Data , Molecular Structure , Proline/chemistry , StereoisomerismABSTRACT
SAR studies on the extension of P3 unit of Boceprevir (1, SCH 503034) with amides and lactams and their synthesis is described. Extensive SAR studies resulted in the identification of 36 bearing 4, 4-dimethyl lactam as the new P4 cap unit with improved potency (K(i)( *)=15nM, EC 90=70nM) and pharmacokinetic properties (Rat AUC (PO)=3.52microMh) compared to 1.
Subject(s)
Amides/chemistry , Antiviral Agents/chemistry , Lactams/chemistry , Oligopeptides/chemistry , Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/pharmacokinetics , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Binding Sites , Crystallography, X-Ray , Lactams/chemical synthesis , Lactams/pharmacokinetics , Oligopeptides/chemical synthesis , Oligopeptides/pharmacokinetics , Proline/analogs & derivatives , Proline/chemistry , Proline/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolismABSTRACT
Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P(4) pocket and optimization of the P(1)' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P(4)-capped inhibitors were also found to have improved PK profile.
Subject(s)
Amides/pharmacology , Drug Discovery , Proline/analogs & derivatives , Serine Proteinase Inhibitors/pharmacology , Serine Proteinase Inhibitors/pharmacokinetics , Viral Nonstructural Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Animals , Binding Sites , Genome, Viral/drug effects , Hepacivirus/drug effects , Hepacivirus/enzymology , Hepacivirus/genetics , Models, Molecular , Molecular Conformation , Proline/chemistry , Proline/pharmacology , RNA, Viral/drug effects , Rats , Serine Proteinase Inhibitors/chemical synthesis , Serine Proteinase Inhibitors/chemistry , Stereoisomerism , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
Extensive SAR studies of the P3 capping group led to the discovery of a series of potent inhibitors with sultam and cyclic sulfonyl urea moieties as the P3 capping. The bicyclic thiophene-sultam or phenyl-sultam cappings were selected for further SAR development. Modification at the P3 side chain determined that the tert-butyl group was the best choice at that position. Optimization of P1 residue significantly improved potency and selectivity. The combination of optimal moieties at all positions led to the discovery of compound 33. This compound had the best overall profile in potency and PK profile: excellent K(i)(*) of 5.3 nM and activity in replicon (EC(90)) of 80 nM, extremely high selectivity of 6100, and a good rat PO AUC of 1.43 microMh.
