ABSTRACT
Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( Kd = 5 nM), potent anti-HCV 2a activity (EC50 = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.
Subject(s)
Cyclophilins/antagonists & inhibitors , Drug Design , Enzyme Inhibitors/pharmacology , Enzyme Inhibitors/pharmacokinetics , Administration, Oral , Antiviral Agents/administration & dosage , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Antiviral Agents/pharmacology , Biological Availability , Cell Line , Cyclophilins/chemistry , Enzyme Inhibitors/administration & dosage , Enzyme Inhibitors/chemistry , Hepacivirus/drug effects , Lactones/administration & dosage , Lactones/chemistry , Lactones/pharmacokinetics , Lactones/pharmacology , Models, Molecular , Protein Conformation , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Spiro Compounds/pharmacokinetics , Spiro Compounds/pharmacologyABSTRACT
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phaseâ 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.
Subject(s)
Protease Inhibitors/chemistry , Quinoxalines/chemistry , Valine/analogs & derivatives , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Cell Line , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Half-Life , Hepacivirus/metabolism , Humans , Microsomes, Liver/metabolism , Protease Inhibitors/pharmacokinetics , Quinoxalines/chemical synthesis , Quinoxalines/pharmacokinetics , Rats , Structure-Activity Relationship , Valine/chemical synthesis , Valine/chemistry , Valine/pharmacokinetics , Viral Nonstructural Proteins/metabolismABSTRACT
In ongoing studies towards novel hepatitisâ C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.
Subject(s)
Protease Inhibitors/chemistry , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Cell Line , Cell Membrane Permeability/drug effects , Cell Proliferation/drug effects , Dogs , Drug Evaluation, Preclinical , Drug Resistance, Viral , Hepacivirus/metabolism , Humans , Hydrogen Bonding , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Rats , Structure-Activity Relationship , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effectsABSTRACT
A second wave of potential SSRIs with high ease of synthetic accessibility were designed based on the reported selective serotonin re-uptake inhibitor litoxetine and our own previous work in this area. Preparation and subsequent optimisation yielded a range of potent and highly selective SSRIs.
Subject(s)
Antidepressive Agents/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Serotonin Plasma Membrane Transport Proteins/chemistry , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Drug Design , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
The reported selective serotonin Re-uptake Inhibitor Litoxetine was used as the starting point in the design of a range of potential SSRIs with high ease of synthetic accessibility. Preparation and subsequent optimization yielded a range of potent and highly selective SSRIs.
Subject(s)
Drug Design , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Cell Line , Humans , Piperidines/chemical synthesis , Piperidines/metabolism , Selective Serotonin Reuptake Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
Optimisation of a series of 4-piperidinyltriazoles led to the identification of compound 28a which showed good whole cell antiviral activity, excellent selectivity over the hERG ion channel and complete oral absorption.
Subject(s)
Anti-HIV Agents/chemical synthesis , Butanes/chemical synthesis , CCR5 Receptor Antagonists , HIV Infections/drug therapy , HIV Infections/metabolism , Piperidines/chemical synthesis , Animals , Anti-HIV Agents/therapeutic use , Butanes/pharmacokinetics , Butanes/therapeutic use , Caco-2 Cells , Cell Line , Dogs , Humans , Piperidines/pharmacokinetics , Piperidines/therapeutic use , Rats , Receptors, CCR5/metabolism , Stereoisomerism , Triazoles/chemical synthesisABSTRACT
The development of a new class of CCR5 antagonist replacing the tropane core of maraviroc by piperidine with a branched N-substituent is described. Compound 15h shows good whole cell antiviral activity together with microsomal stability and only weak activity at the hERG ion channel.
