ABSTRACT
Mounting evidence from the literature suggests that blocking S1P2 receptor (S1PR2) signaling could be effective for the treatment of idiopathic pulmonary fibrosis (IPF). However, only a few antagonists have been so far disclosed. A chemical enablement strategy led to the discovery of a pyridine series with good antagonist activity. A pyridazine series with improved lipophilic efficiency and with no CYP inhibition liability was identified by scaffold hopping. Further optimization led to the discovery of 40 (GLPG2938), a compound with exquisite potency on a phenotypic IL8 release assay, good pharmacokinetics, and good activity in a bleomycin-induced model of pulmonary fibrosis.
Subject(s)
Drug Design , Idiopathic Pulmonary Fibrosis/drug therapy , Pyridazines/chemistry , Pyridazines/pharmacology , Sphingosine-1-Phosphate Receptors/antagonists & inhibitors , Animals , CHO Cells , Cricetulus , Humans , Idiopathic Pulmonary Fibrosis/metabolism , Interleukin-8/metabolism , Male , Mice , Pyridazines/pharmacokinetics , Pyridazines/therapeutic use , Structure-Activity Relationship , Tissue DistributionABSTRACT
Cystic fibrosis (CF) is a life-threatening recessive genetic disease caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Lumacaftor, it has been shown that administration of one or more small molecules can partially restore the CFTR function. Correctors are small molecules that enhance the amount of CFTR on the cell surface, while potentiators improve the gating function of the CFTR channel. Herein, we describe the discovery and optimization of a novel potentiator series. Scaffold hopping, focusing on retaining the different intramolecular contacts, was crucial in the whole discovery process to identify a novel series devoid of genotoxic liabilities. From this series, the clinical candidate GLPG2451 was selected based on its pharmacokinetic properties, allowing QD dosing and based on its low CYP induction potential.
Subject(s)
Cystic Fibrosis/drug therapy , Drug Discovery , Pyridines/pharmacology , Pyridines/therapeutic use , Animals , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Humans , Pyridines/chemistry , Pyridines/pharmacokinetics , RatsABSTRACT
Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described.
Subject(s)
Chloride Channel Agonists/chemistry , Cystic Fibrosis/drug therapy , Drug Discovery , Mutant Proteins/drug effects , Aminophenols/pharmacokinetics , Animals , Chloride Channel Agonists/pharmacokinetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Humans , Mutation , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Quinolones/pharmacokinetics , Rats , Structure-Activity RelationshipABSTRACT
Triazolinylidenes promote γ-selective C-carboxylation (up to 99 : 1 regioselectivity) in the O- to C-carboxyl transfer of furanyl carbonates in contrast to DMAP that promotes preferential α-C-carboxylation with moderate regiocontrol (typically 60 : 40 regioselectivity). The generality of this process is described and a simple mechanistic and kinetic model postulated to account for the observed regioselectivity.
Subject(s)
4-Butyrolactone/analogs & derivatives , Carbon/chemistry , Carbonates/chemistry , Furans/chemistry , Oxygen/chemistry , 4-Aminopyridine/analogs & derivatives , 4-Aminopyridine/chemistry , 4-Butyrolactone/chemistry , Catalysis , Kinetics , Lewis Bases , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
The structural motif within a series of tetrahydropyrimidine-based isothioureas necessary for generating high asymmetric induction in the asymmetric Steglich rearrangement of oxazolyl carbonates is fully explored, with crossover and dynamic (19)Fâ NMR experiments used to develop a mechanistic understanding of this transformation.
Subject(s)
Carbonates/chemistry , Lewis Bases/chemistry , Oxazoles/chemistry , Pyrimidines/chemistry , Thiourea/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Molecular Structure , StereoisomerismABSTRACT
Rate and equilibrium constants for the reactions of a series of isothioureas with benzhydrylium ions have been measured photometrically. The data were employed to determine the nucleophilicities and nucleofugalities of isothioureas and compare them with those of other organocatalysts.
ABSTRACT
The catalytic activity and enantioselectivity in the kinetic resolution of (±)-1-naphthylethanol with a range of structurally related 3,4-dihydropyrimido[2,1-b]benzothiazole-based catalysts is examined. Of the isothiourea catalysts screened, (2S,3R)-2-phenyl-3-isopropyl substitution proved optimal, giving good levels of selectivity in the kinetic resolution of a number of secondary alcohols (S values up to >100 at ~50% conversion). Low catalyst loadings (0.10-0.25 mol%) of the optimal isothiourea can be used to generate enantiopure alcohols (>99% ee) in good yields.
Subject(s)
Benzothiazoles/chemistry , Thiourea/chemistry , Acylation , Amines/chemistry , Catalysis , Molecular Structure , StereoisomerismABSTRACT
The structural requirements of amidines necessary to act as efficient O- to C-carboxyl transfer agents are delineated and the scope of this process outlined through its application to a range of oxazolyl, benzofuranyl and indolyl carbonates.