ABSTRACT
The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
Subject(s)
Antiviral Agents/pharmacology , Enzyme Inhibitors/pharmacology , Hepacivirus/drug effects , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Virus Replication/drug effects , Animals , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Area Under Curve , Carbamates , Dogs , Drug Discovery , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacokinetics , Hepacivirus/enzymology , Hepacivirus/physiology , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Magnetic Resonance Spectroscopy , Pyrrolidines , Rats , Spectrometry, Mass, Electrospray Ionization , Structure-Activity Relationship , Valine/analogs & derivativesABSTRACT
Spiropiperidine indoline-substituted diaryl ureas had been identified as antagonists of the P2Y1 receptor. Enhancements in potency were realized through the introduction of a 7-hydroxyl substitution on the spiropiperidinylindoline chemotype. SAR studies were conducted to improve PK and potency, resulting in the identification of compound 3e, a potent, orally bioavailable P2Y1 antagonist with a suitable PK profile in preclinical species. Compound 3e demonstrated a robust antithrombotic effect in vivo and improved bleeding risk profile compared to the P2Y12 antagonist clopidogrel in rat efficacy/bleeding models.
Subject(s)
Phenylurea Compounds/chemistry , Platelet Aggregation Inhibitors/chemistry , Purinergic P2Y Receptor Antagonists/chemistry , Receptors, Purinergic P2Y1/chemistry , Thiazoles/chemistry , Urea/analogs & derivatives , Administration, Oral , Animals , Dogs , Half-Life , Macaca fascicularis , Phenylurea Compounds/pharmacokinetics , Phenylurea Compounds/pharmacology , Phenylurea Compounds/therapeutic use , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/pharmacokinetics , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation Inhibitors/therapeutic use , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacology , Purinergic P2Y Receptor Antagonists/therapeutic use , Rats , Receptors, Purinergic P2Y1/metabolism , Structure-Activity Relationship , Thiazoles/pharmacokinetics , Thiazoles/pharmacology , Thiazoles/therapeutic use , Thrombosis/drug therapy , Urea/pharmacokinetics , Urea/pharmacology , Urea/therapeutic useABSTRACT
Cyclodehydration using the Burgess reagent provided a novel approach toward the synthesis of N-bridged 5,6-bicylic pyridines including pyrolo-, imidazo-, and triazolopyridines under mild and neutral conditions. The methodology tolerates acid-sensitive functional groups. A novel addition product was observed between the resulting pyrrolo- or imidazopyridine and an additional equivalent of the Burgess reagent, producing the corresponding sulfonylcarbamate adduct.
Subject(s)
Carbamates/chemistry , Heterocyclic Compounds, 2-Ring/chemistry , Pyridines/chemical synthesis , Sulfur Compounds/chemistry , Water/chemistry , Crystallography, X-Ray , Cyclization , Models, Molecular , Molecular Structure , Pyridines/chemistryABSTRACT
(S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide (2) was synthesized as an orally bioavailable KCNQ2 potassium channel opener. In a rat model of migraine, 2 demonstrated significant oral activity in reducing the total number of cortical spreading depressions induced by potassium chloride.
Subject(s)
Acrylamides/chemical synthesis , Cerebral Cortex/drug effects , Migraine Disorders/physiopathology , Morpholines/chemical synthesis , Potassium Channels/drug effects , Acrylamides/chemistry , Acrylamides/pharmacology , Administration, Oral , Animals , Biological Availability , Cell Line , Cerebral Cortex/physiopathology , Disease Models, Animal , Dogs , Humans , Ion Channel Gating , KCNQ2 Potassium Channel , Migraine Disorders/metabolism , Morpholines/chemistry , Morpholines/pharmacology , Oocytes/drug effects , Oocytes/physiology , Patch-Clamp Techniques , Potassium Channels/physiology , Potassium Channels, Voltage-Gated , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Xenopus laevisABSTRACT
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of Candida albicans, Candida glabrata, and Cryptococcus neoformans.
