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1.
J Med Chem ; 63(13): 7163-7185, 2020 07 09.
Article in English | MEDLINE | ID: mdl-32511913

ABSTRACT

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.


Subject(s)
Dermatitis, Atopic/drug therapy , Dermatologic Agents/pharmacology , Drug Design , Janus Kinase Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Pyrroles/pharmacology , Dermatologic Agents/therapeutic use , Humans , Inhibitory Concentration 50 , Janus Kinase Inhibitors/therapeutic use , Janus Kinases/chemistry , Models, Molecular , Protein Conformation , Pyrroles/therapeutic use
2.
Bioorg Med Chem Lett ; 29(7): 873-877, 2019 04 01.
Article in English | MEDLINE | ID: mdl-30755337

ABSTRACT

Optimization of novel azetidine compounds, which we had found as colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors, provided JTE-952 as a clinical candidate with high cellular activity (IC50 = 20 nM) and good pharmacokinetics profile. JTE-952 was also effective against a mouse collagen-induced model of arthritis (mouse CIA-model). Additionally, the X-ray co-crystal structure of JTE-952 with CSF-1R protein was shown to be a Type II inhibitor, and the kinase panel assay indicated that JTE-952 had high kinase selectivity.


Subject(s)
Arthritis, Experimental/drug therapy , Azetidines/chemistry , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Animals , Azetidines/pharmacology , Collagen/toxicity , Gene Expression Regulation/drug effects , Humans , Mice , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology
3.
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
4.
Bioorg Med Chem Lett ; 29(1): 115-118, 2019 01 01.
Article in English | MEDLINE | ID: mdl-30442420

ABSTRACT

We report the discovery of a novel azetidine scaffold for colony stimulating factor-1 receptor (CSF-1R) Type II inhibitors by using a structure-based drug design (SBDD) based on a docking model. The work leads to the representative compound 4a with high CSF-1R inhibitory activity (IC50 = 9.1 nM). The obtained crystal structure of an azetidine compound with CSF-1R, which matched our predicted docking model, demonstrates that the azetidine compounds bind to the DFG-out conformation of the protein as a Type II inhibitor.


Subject(s)
Azetidines/pharmacology , Drug Discovery , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors , Azetidines/chemical synthesis , Azetidines/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Structure-Activity Relationship
5.
ACS Med Chem Lett ; 8(12): 1320-1325, 2017 Dec 14.
Article in English | MEDLINE | ID: mdl-29259755

ABSTRACT

Inhibition of hypoxia inducible factor prolyl hydroxylase (PHD) represents a promising strategy for the discovery of a next generation treatment for renal anemia. We identified several 5,6-fused ring systems as novel scaffolds of the PHD inhibitor on the basis of pharmacophore analysis. In particular, triazolopyridine derivatives showed potent PHD2 inhibitory activities. Examination of the predominance of the triazolopyridines in potency by electrostatic calculations suggested favorable π-π stacking interactions with Tyr310. Lead optimization to improve the efficacy of erythropoietin release in cells and in vivo by improving cell permeability led to the discovery of JTZ-951 (compound 14), with a 5-phenethyl substituent on the triazolopyridine group, which increased hemoglobin levels with daily oral dosing in rats. Compound 14 was rapidly absorbed after oral administration and disappeared shortly thereafter, which could be advantageous in terms of safety. Compound 14 was selected as a clinical candidate.

6.
ACS Med Chem Lett ; 7(1): 23-7, 2016 Jan 14.
Article in English | MEDLINE | ID: mdl-26819660

ABSTRACT

A novel series of RORγ inhibitors was identified starting with the HTS hit 1. After SAR investigation based on a prospective consideration of two drug-likeness metrics, ligand efficiency (LE) and fraction of sp(3) carbon atoms (Fsp(3)), significant improvement of metabolic stability as well as reduction of CYP inhibition was observed, which finally led to discovery of a selective and orally efficacious RORγ inhibitor 3z.

7.
J Med Chem ; 54(8): 2839-63, 2011 Apr 28.
Article in English | MEDLINE | ID: mdl-21417219

ABSTRACT

Aggrecanases, particularly aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5), are believed to be key enzymes involved in the articular cartilage breakdown that leads to osteoarthritis. Thus, aggrecanases are considered to be viable drug targets for the treatment of this debilitating disease. A series of (1S,2R,3R)-2,3-dimethyl-2-phenyl-1-sulfamidocyclopropanecarboxylates was discovered to be potent, highly selective, and orally bioavailable aggrecanase inhibitors. These compounds have unique P1' groups comprising novel piperidine- or piperazine-based heterocycles that are connected to a cyclopropane amino acid scaffold via a sulfamido linkage. These P1' groups are quite effective in imparting selectivity over other MMPs, and this selectivity was further increased by incorporation of a methyl substituent in the 2-position of the cyclopropane ring. In contrast to classical hydroxamate-based inhibitors that tend to lack metabolic stability, our aggrecanase inhibitors bear a carboxylate zinc-binding group and have good oral bioavailability. Lead compound 13b, characterized by the novel P1' portion of 1,2,3,4-tetrahydropyrido[3',4':4,5]imidazo[1,2-a]pyridine ring, is a potent and selective aggrecanse inhibitor with excellent pharmacokinetic profiles.


Subject(s)
Cyclopropanes/chemistry , Cyclopropanes/pharmacology , Drug Discovery , Endopeptidases/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Animals , Crystallography, X-Ray , Cyclopropanes/pharmacokinetics , Enzyme Inhibitors/pharmacokinetics , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Mice , Mice, Knockout , Models, Molecular , Structure-Activity Relationship
8.
J Med Chem ; 49(24): 6950-3, 2006 Nov 30.
Article in English | MEDLINE | ID: mdl-17125247

ABSTRACT

We report a new series of hepatitis C virus NS5B RNA polymerase inhibitors containing a conformationally constrained tetracyclic scaffold. SAR studies led to the identification of 6,7-dihydro-5H-benzo[5,6][1,4]diazepino[7,1-a]indoles (19 and 20) bearing a basic pendent group with high biochemical and cellular potencies. These compounds displayed a very small shift in cellular potency when the replicon assay was performed in the presence of human serum albumin.


Subject(s)
Antiviral Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Hepacivirus/enzymology , Heterocyclic Compounds, 4 or More Rings/chemical synthesis , Indoles/chemical synthesis , Viral Nonstructural Proteins/antagonists & inhibitors , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Benzodiazepines/chemistry , Benzodiazepines/pharmacology , Crystallography, X-Ray , Hepacivirus/genetics , Heterocyclic Compounds, 4 or More Rings/chemistry , Heterocyclic Compounds, 4 or More Rings/pharmacology , Humans , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Molecular Conformation , RNA, Viral/genetics , Replicon , Serum Albumin , Structure-Activity Relationship , Viral Nonstructural Proteins/chemistry
9.
Bioorg Med Chem ; 14(17): 5781-94, 2006 Sep 01.
Article in English | MEDLINE | ID: mdl-16762554

ABSTRACT

Conformationally restricted 3-anilino-4-(3-indolyl)maleimide derivatives were designed and synthesized aiming at discovery of novel protein kinase Cbeta (PKCbeta)-selective inhibitors possessing oral bioavailability. Among them, compounds having a fused five-membered ring at the indole 1,2-position inhibited PKCbeta2 with IC50 of nM-order and showed good oral bioavailability. One of the most potent compounds was found to be PKCbeta-selective over other 6 isozymes and exhibited ameliorative effects in a rat diabetic retinopathy model via oral route.


Subject(s)
Maleimides/chemistry , Maleimides/pharmacology , Protein Kinase C/antagonists & inhibitors , Administration, Oral , Animals , Biological Availability , Diabetes Mellitus, Experimental/drug therapy , Diabetic Retinopathy/drug therapy , Dose-Response Relationship, Drug , Maleimides/pharmacokinetics , Maleimides/therapeutic use , Molecular Structure , Protein Kinase C/metabolism , Protein Kinase C beta , Rats , Structure-Activity Relationship
10.
J Med Chem ; 48(10): 3586-604, 2005 May 19.
Article in English | MEDLINE | ID: mdl-15887966

ABSTRACT

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 exhibited potent inhibitory activity against factor Xa (FXa) and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkeys, showed a dose-dependent antithrombotic effect at 0.1, 0.3, and 1 mg kg(-1) h(-1) in a rat model of venous thrombosis, and significantly reduced the size of brain infarction in a middle cerebral artery occlusion model at a dose of 0.1 mg kg(-1) h(-1). These results suggest that compound 2 (JTV-803) is likely to be useful as both a venous and arterial antithrombotic agent.


Subject(s)
Factor Xa Inhibitors , Fibrinolytic Agents/chemical synthesis , Isoquinolines/chemical synthesis , Piperidines/chemical synthesis , Pyridines/chemical synthesis , Tetrahydroisoquinolines/chemical synthesis , Administration, Oral , Animals , Arterial Occlusive Diseases/complications , Brain Infarction/drug therapy , Brain Infarction/etiology , Brain Infarction/pathology , Cerebral Arterial Diseases/complications , Factor Xa/chemistry , Fibrinolytic Agents/chemistry , Fibrinolytic Agents/pharmacology , Humans , Injections, Intravenous , Isoquinolines/chemistry , Isoquinolines/pharmacology , Macaca fascicularis , Middle Cerebral Artery , Models, Molecular , Piperidines/chemistry , Piperidines/pharmacology , Pyridines/chemistry , Pyridines/pharmacology , Rats , Structure-Activity Relationship , Tetrahydroisoquinolines/chemistry , Tetrahydroisoquinolines/pharmacology , Venous Thrombosis/drug therapy
11.
Bioorg Med Chem Lett ; 15(1): 185-9, 2005 Jan 03.
Article in English | MEDLINE | ID: mdl-15582437

ABSTRACT

A series of novel 2,7-disubstituted tetrahydroisoquinoline derivatives were designed and synthesized. Among these derivatives, compounds 1 and 2 (JTV-803) exhibited potent inhibitory activity against FXa and good selectivity with respect to other serine proteases (thrombin, plasmin, and trypsin). In addition, compound 2 exhibited potent anti-FXa activity after intravenous and oral administration to cynomolgus monkey, and showed a dose-dependent antithrombotic effect in a rat model of venous thrombosis.


Subject(s)
Factor Xa Inhibitors , Serine Proteinase Inhibitors/pharmacology , Tetrahydroisoquinolines/pharmacology , Animals , Rats , Serine Proteinase Inhibitors/therapeutic use , Tetrahydroisoquinolines/therapeutic use , Venous Thrombosis/drug therapy , Venous Thrombosis/enzymology
12.
Bioorg Med Chem Lett ; 14(16): 4281-6, 2004 Aug 16.
Article in English | MEDLINE | ID: mdl-15261287

ABSTRACT

A series of benzimidazole derivatives with the side chain on the nitrogen atom oriented to the prime site of factor Xa (FXa) were designed and synthesized. Compounds with substituted aminocarbonylmethyl groups as the side chain showed potent FXa inhibitory activity. Compounds 1 and 2 exhibited most potent inhibitory activity and were effective as anticoagulants in a DIC model.


Subject(s)
Benzimidazoles/chemistry , Factor Xa Inhibitors , Serine Proteinase Inhibitors/chemistry , Serine Proteinase Inhibitors/pharmacology , Structure-Activity Relationship
13.
J Med Chem ; 47(1): 101-9, 2004 Jan 01.
Article in English | MEDLINE | ID: mdl-14695824

ABSTRACT

A variety of novel heterocyclic compounds having thienoazepine, pyrroloazepine, furoazepine, and thienodiazepine skeletons were synthesized, most of which exhibited potent antagonism of [(3)H]-AVP specific binding in assays using rat liver (V1), rat kidney (V2), human platelet plasma membranes, and recombinant human CHO cells (V2), as well as antagonizing AVP-induced hypertension in rats (V1, intravenous) and showing a diuretic effect in rats (V2, oral). By detailed studies of the structure-activity relationships of these compounds, the thienoazepine derivative 1 was found to be a very potent combined V1 and V2 antagonist. After further pharmacological and toxicological evaluation as well as physical properties, the hydrochloride 2 (JTV-605) of compound 1 was selected for clinical studies as a potent AVP antagonist with a long duration of action.


Subject(s)
Antidiuretic Hormone Receptor Antagonists , Arginine Vasopressin/antagonists & inhibitors , Azepines/chemical synthesis , Benzamides/chemical synthesis , Thiophenes/chemical synthesis , Animals , Azepines/chemistry , Azepines/pharmacology , Benzamides/chemistry , Benzamides/pharmacology , Binding, Competitive , Blood Platelets/drug effects , Blood Platelets/metabolism , CHO Cells , Cricetinae , Humans , Hypertension/drug therapy , In Vitro Techniques , Kidney/drug effects , Kidney/metabolism , Liver/drug effects , Liver/metabolism , Male , Membranes , Models, Molecular , Radioligand Assay , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiophenes/chemistry , Thiophenes/pharmacology
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