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1.
J Med Chem ; 67(2): 952-970, 2024 01 25.
Article in English | MEDLINE | ID: mdl-38170624

ABSTRACT

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

2.
Biochemistry ; 62(14): 2161-2169, 2023 07 18.
Article in English | MEDLINE | ID: mdl-37414577

ABSTRACT

Tyrosine phosphorylation is an essential post-translational modification that regulates various biological events and is implicated in many diseases including cancer and atherosclerosis. Vascular endothelial protein tyrosine phosphatase (VE-PTP), which plays an important role in vascular homeostasis and angiogenesis, is therefore an attractive drug target for these diseases. However, there are still no drugs targeting PTP including VE-PTP. In this paper, we report the discovery of a novel VE-PTP inhibitor, Cpd-2, by fragment-based screening combining various biophysical techniques. Cpd-2 is the first VE-PTP inhibitor with a weakly acidic structure and high selectivity, unlike known strongly acidic inhibitors. We believe that this compound represents a new possibility for the development of bioavailable VE-PTP inhibitors.


Subject(s)
Enzyme Inhibitors , Receptor-Like Protein Tyrosine Phosphatases, Class 3 , Receptor-Like Protein Tyrosine Phosphatases, Class 3/metabolism , Phosphorylation
3.
Bioorg Med Chem ; 44: 116283, 2021 08 15.
Article in English | MEDLINE | ID: mdl-34274549

ABSTRACT

A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.


Subject(s)
Adenosine Triphosphate/antagonists & inhibitors , Drug Discovery , Indoles/pharmacology , Protein Kinase Inhibitors/pharmacology , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Binding Sites/drug effects , Dose-Response Relationship, Drug , Humans , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyruvate Dehydrogenase Acetyl-Transferring Kinase/metabolism , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 30(17): 127361, 2020 09 01.
Article in English | MEDLINE | ID: mdl-32738974

ABSTRACT

A novel unsymmetrical structural class of orally bioavailable hepatitis C virus (HCV) nonstructural 5A protein (NS5A) inhibitors has been generated by improving both the solubility and membrane permeability of the lead compound found in our previous work. The representative compound 14, with a 5-hydroxymethylpyrazine group and a 3-t-butylpropargyl group on each side of the molecule, exhibited the best oral bioavailability in this study, inhibiting not only the HCV genotype 1a, 1b, 2a, and 3a replicons with EC50 values in the picomolar range, but also inhibited 1a Q30 mutants induced by launched symmetrical inhibitors with EC50 values in the low nanomolar range.


Subject(s)
Antiviral Agents/chemistry , Hepacivirus/metabolism , Viral Nonstructural Proteins/antagonists & inhibitors , Administration, Oral , Antiviral Agents/metabolism , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Genotype , Hepacivirus/genetics , Hepatitis C/drug therapy , Hepatitis C/pathology , Hepatitis C/virology , Humans , Mutation , Pargyline/chemistry , Pyrazines/chemistry , Structure-Activity Relationship , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
5.
Bioorg Med Chem Lett ; 30(5): 126932, 2020 03 01.
Article in English | MEDLINE | ID: mdl-31952964

ABSTRACT

A novel unsymmetrical structural class of HCV NS5A inhibitors showing picomolar range antiviral activity has been identified. An unsymmetrical lead compound 2, generated from a substructure of a known symmetrical inhibitor 1, was optimized by extension of its substituents to interact with the hitherto unexplored site of the target protein. This approach afforded novel highly potent unsymmetrical inhibitor 20, which not only equally inhibited HCV genotypes1a, 1b, and 2a with EC50 values in the picomolar range, but also inhibited the 1a Q30K mutant induced by a launched symmetrical inhibitor daclatasvir with an EC50 in the low nanomolar range.


Subject(s)
Antiviral Agents/pharmacology , Glycine/analogs & derivatives , Glycine/pharmacology , Hepacivirus/chemistry , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemical synthesis , Cell Line, Tumor , Humans , Imidazoles/chemical synthesis , Microbial Sensitivity Tests , Molecular Structure
6.
J Med Chem ; 62(5): 2837-2842, 2019 03 14.
Article in English | MEDLINE | ID: mdl-30776227

ABSTRACT

Starting from a previously reported RORγ inhibitor (1), successive efforts to improve in vivo potency were continued. Introduction of metabolically beneficial motifs in conjunction with scaffold hopping was examined, resulting in discovery of the second generation RORγ inhibitor composed of a 4-(isoxazol-3-yl)butanoic acid scaffold (24). Compound 24 achieved a 10-fold improvement in in vivo potency in a mouse CD3 challenge model along with significant anti-inflammatory effects in a mouse dermatitis model.


Subject(s)
Azoles/pharmacology , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Animals , Azoles/chemistry , Dermatitis/drug therapy , Disease Models, Animal , Drug Discovery , Mice , Molecular Docking Simulation , Structure-Activity Relationship
7.
Org Lett ; 7(23): 5143-6, 2005 Nov 10.
Article in English | MEDLINE | ID: mdl-16268523

ABSTRACT

[reaction, structure: see text] Conjugate addition of various prochiral nitroalkanes to cyclic alpha,beta-unsaturated ketones was found to be efficiently catalyzed by N-spiro C2-symmetric chiral quaternary ammonium bromide 1b possessing a 3,5-bis(3,4,5-trifluorophenyl)phenyl substituent under solid-liquid phase-transfer conditions to afford the corresponding gamma-nitro ketones in excellent chemical yields with unprecedented levels of diastereo- and enantiocontrol.

8.
J Am Chem Soc ; 126(38): 11790-1, 2004 Sep 29.
Article in English | MEDLINE | ID: mdl-15382903

ABSTRACT

Highly enantioselective conjugate addition of nitroalkanes to alkylidenemalonates has been accomplished for the first time by the utilization of efficient phase-transfer catalysis of N-spiro C2-symmetric chiral quaternary ammonium bromide 1. For instance, simple mixing of nitropropane (2, R1 = Et), diisopropyl benzylidienemalonate (3, R2 = Ph), Cs2CO3 (1 equiv), and (S,S)-1 (1 mol %) in toluene at 0 degrees C for 2.5 h gave rise to the desired conjugate addition product 4 (R1 = Et, R2 = Ph) quantitatively (anti/syn = 86:14) with 97% ee (anti isomer). The applicability of this procedure has been demonstrated with other representative alkylidenemalonates and nitroalkanes. Since 4 can be readily transformed into the corresponding gamma-amino acid hydrochloride 5 without loss of diastereo- and enantioselectivity, the present method provides a new and practical access to various optically active gamma-amino acid derivatives.

9.
J Am Chem Soc ; 126(31): 9558-9, 2004 Aug 11.
Article in English | MEDLINE | ID: mdl-15291557

ABSTRACT

Direct catalytic asymmetric Michael addition reactions of ketones to nitroolefins using newly developed chiral pyrrolidine-pyridine conjugate bases as catalysts are described. The desired 1,4-adducts are obtained in excellent yields with high enantio- and diastereoselectivities.

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