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1.
ACS Med Chem Lett ; 12(1): 121-128, 2021 Jan 14.
Article in English | MEDLINE | ID: mdl-33488973

ABSTRACT

Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating ß-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating ß-thalassemia and sickle cell disease.

2.
Bioorg Med Chem Lett ; 30(20): 127475, 2020 10 15.
Article in English | MEDLINE | ID: mdl-32781218

ABSTRACT

The discovery and optimization of a novel series of G9a/GLP (EHMT2/1) inhibitors are described. Starting from known G9a/GLP inhibitor 5, efforts to explore the structure-activity relationship and optimize drug properties led to a novel compound 13, the side chain of which was converted to tetrahydroazepine. Compound 13 showed increased G9a/GLP inhibitory activity compared with compound 5. In addition, compound 13 exhibited improved human ether-a-go-go related gene (hERG) inhibitory activity over compound 5 and also improved pharmacokinetic profile in mice (oral bioavailability: 17 to 40%). Finally, the co-crystal structure of G9a in complex with compound 13 provides the basis for the further development of tetrahydroazepine-based G9a/GLP inhibitors.


Subject(s)
Drug Discovery , Enzyme Inhibitors/pharmacology , Histone-Lysine N-Methyltransferase/antagonists & inhibitors , Pyrimidines/pharmacology , Animals , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/genetics , Ether-A-Go-Go Potassium Channels/metabolism , Histocompatibility Antigens/metabolism , Histone-Lysine N-Methyltransferase/metabolism , Humans , Mice , Molecular Structure , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Structure-Activity Relationship
3.
Bioorg Med Chem Lett ; 30(19): 127425, 2020 10 01.
Article in English | MEDLINE | ID: mdl-32717372

ABSTRACT

Pharmacological reactivation of the γ-globin gene for the production of fetal hemoglobin (HbF) is a promising approach for the management of ß-thalassemia and sickle cell disease (SCD). We conducted a phenotypic screen in human erythroid progenitor cells to identify molecules that could induce HbF, which resulted in identification of the hit compound 1. Exploration of structure-activity relationships and optimization of ADME properties led to 2-azaspiro[3.3]heptane derivative 18, which is more rigid and has a unique structure. In vivo using cynomolgus monkeys, compound 18 induced a significant dose-dependent increase in globin switching, with developable properties. Moreover, compound 18 showed no genotoxic effects and was much safer than hydroxyurea. These findings could facilitate the development of effective new therapies for the treatment of ß-hemoglobinopathies, including SCD.


Subject(s)
Azetidines/pharmacology , Erythroid Precursor Cells/drug effects , Fetal Hemoglobin/metabolism , Spiro Compounds/pharmacology , Animals , Azetidines/chemical synthesis , Azetidines/pharmacokinetics , Drug Design , Drug Stability , Gene Expression Regulation/drug effects , Humans , Isoxazoles/chemical synthesis , Isoxazoles/pharmacokinetics , Isoxazoles/pharmacology , Macaca fascicularis , Microsomes, Liver/metabolism , Molecular Structure , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacokinetics , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 30(16): 127299, 2020 08 15.
Article in English | MEDLINE | ID: mdl-32631519

ABSTRACT

Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure-activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1.


Subject(s)
Drug Design , Indoles/pharmacology , Oligodendrocyte Precursor Cells/drug effects , Spiro Compounds/pharmacology , Animals , Cell Differentiation , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Molecular Structure , Rats , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship
5.
Bioorg Med Chem ; 28(6): 115348, 2020 03 15.
Article in English | MEDLINE | ID: mdl-32046916

ABSTRACT

A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC50 = 0.0032 µM). Furthermore, oral administration of compound 18 significantly decreased clinical severity in an experimental autoimmune encephalomyelitis (EAE) model.


Subject(s)
Drug Discovery , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Indoles/pharmacology , Oligodendrocyte Precursor Cells/drug effects , Spiro Compounds/pharmacology , Animals , Cell Differentiation/drug effects , Dose-Response Relationship, Drug , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Indoles/chemical synthesis , Indoles/chemistry , Mice , Mice, Inbred C57BL , Molecular Structure , Rats , Rats, Wistar , Spiro Compounds/chemical synthesis , Spiro Compounds/chemistry , Structure-Activity Relationship
6.
Biochem Pharmacol ; 171: 113717, 2020 01.
Article in English | MEDLINE | ID: mdl-31751536

ABSTRACT

Heritable disorders associated with hemoglobin production are the most common monogenic disorders. These are mainly represented by disorders such as ß-thalassemia and sickle cell disease. Induction of fetal hemoglobin (HbF) has been known to ameliorate the clinical severity of these ß hemoglobinopathies. A high throughput phenotypic screening was used in this study to isolate novel compounds that may enhance the expression of γ-globin, the component of HbF, in human erythroid cell lines and primary erythroid progenitors derived from human CD34+ cells. The effect of lead compounds on epigenetic enzymes and key transcriptional factors was evaluated to identify their mode of action. One hit compound was further evaluated in vivo using monkey models. Among the ~18,000 compounds screened, 18 compounds were selected and tested to determine their ability to induce HbF in human erythroid cell lines and primary erythroid cells. One of these compounds, a 3-phenyl-isoxazole derivative, could potentially induce HbF in monkey bone marrow cells when administered orally. The compound downregulated negative transcriptional regulators of HbF, Bcl11a and LRF without inhibiting the known epigenetic enzymes. These studies demonstrated the advantages associated with phenotype-screening and identified novel fetal globin inducers that may be useful for treating hemoglobinopathies.


Subject(s)
Fetal Hemoglobin/genetics , Gene Expression Regulation/drug effects , Hemoglobinopathies/genetics , Repressor Proteins/genetics , Xenobiotics/pharmacology , Zinc Fingers , Animals , Antigens, CD34/metabolism , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line , Down-Regulation/drug effects , Erythroblasts/cytology , Erythroblasts/drug effects , Erythroblasts/metabolism , Fetal Hemoglobin/metabolism , Hemoglobinopathies/metabolism , High-Throughput Screening Assays/methods , Humans , Macaca fascicularis , Phenotype , Repressor Proteins/metabolism
7.
J Org Chem ; 79(6): 2580-90, 2014 Mar 21.
Article in English | MEDLINE | ID: mdl-24555872

ABSTRACT

The second-generation total synthesis of quinaldopeptin (1) was established via a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence and a racemization-free [5 + 5] coupling and macrolactamization. A single-crystal X-ray structure of the chromophore analogue 26 confirmed the structural and stereochemical assignments of the macrocycle. Synthetic 1 successfully unwound supercoiled DNA to form a relaxed DNA in a dose-dependent manner, the binding affinity of 1 to four dsODNs was within a similar range (K(b) = 1.45-2.53 × 10(7) M(-1)), and the sequence selectivity was subtle. It was suggested that 1 possesses biological behaviors similar to those of sandramycin (2) in terms of cytotoxic activity against human cancer cell lines (IC50 = 3.2-12 nM) and HIF-1 inhibitory activity.


Subject(s)
DNA/chemistry , Echinomycin/analogs & derivatives , Hypoxia-Inducible Factor 1/antagonists & inhibitors , Hypoxia-Inducible Factor 1/chemistry , Cell Line , Crystallography, X-Ray , DNA/drug effects , Echinomycin/chemical synthesis , Echinomycin/chemistry , Echinomycin/pharmacology , Humans , Inhibitory Concentration 50 , Molecular Structure , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology
8.
Org Lett ; 16(2): 428-31, 2014 Jan 17.
Article in English | MEDLINE | ID: mdl-24341513

ABSTRACT

The total synthesis of sandramycin has been accomplished by using a Staudinger/aza-Wittig/diastereoselective Ugi three-component reaction sequence as a key step to obtain a linear pentadepsipeptide. Subsequent [5 + 5] coupling of the penptapeptide, macrolactamization, and introduction of the quinaldin chromophores afforded sandramycin. Dihydroxy and diacetoxy analogues were also prepared, and the cytotoxic activity of these analogues against a range of human cancer cell lines was evaluated.


Subject(s)
Antineoplastic Agents/chemical synthesis , Depsipeptides/chemical synthesis , Gram-Positive Bacteria/chemistry , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Base Sequence , Cyclization , DNA/drug effects , Depsipeptides/chemistry , Depsipeptides/pharmacology , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Structure-Activity Relationship
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