ABSTRACT
Inhibition of the hypoxia-inducible factor prolyl hydroxylase (HIF-PHD) represents a promising strategy for discovering next-generation treatments for renal anemia. We discovered DS44470011 in our previous study, which showed potent in vitro activity and in vivo efficacy based on HIF-PHD inhibition. However, DS44470011 was also found to exert genotoxic effects. By converting the biphenyl structure, which is suspected to be the cause of this genotoxicity, to a 1-phenylpiperidine structure, we were able to avoid genotoxicity and further improve the in vitro activity and in vivo efficacy. Furthermore, through the optimization of pyrimidine derivatives, we discovered DS-1093a, which has a wide safety margin with potent in vitro activity and an optimal pharmacokinetic profile. DS-1093a achieved an increase in hemoglobin levels in an adenine-induced rat model of chronic kidney disease after its continuous administration for 4 days.
ABSTRACT
Trophoblast cell surface antigen 2 (TROP2) is highly expressed on various epithelial tumors and correlates with poor prognosis. We developed the novel TROP2-directed antibody-drug conjugate (ADC), datopotamab deruxtecan (Dato-DXd, DS-1062a), with a potent DNA topoisomerase I inhibitor (DXd), and evaluated its antitumor activity and safety profiles in preclinical models.The pharmacologic activity and mechanism of action of Dato-DXd were investigated in several human cancer cell lines and xenograft mouse models including patient-derived xenograft (PDX) models. Safety profiles were also assessed in rats and cynomolgus monkeys.Dato-DXd bound specifically to TROP2 and was internalized into tumor cells followed by intracellular trafficking to lysosome and DXd release, which induced DNA damage and apoptosis in TROP2-expressing tumor cells in vitro. Dato-DXd exhibited in vivo antitumor activity with DNA damage induced by the accumulated DXd in TROP2-expressing xenograft tumors, but neither isotype control IgG-ADC nor anti-TROP2 antibody had this effect. Dato-DXd also showed potent antitumor activity with tumor regression in several TROP2-expressing xenograft tumors including NSCLC PDX models. Safety profiles of Dato-DXd in rats and cynomolgus monkeys were acceptable.Dato-DXd demonstrated potent antitumor activity against TROP2-expressing tumors by efficient payload delivery into tumors and acceptable safety profiles in preclinical models. These results suggest Dato-DXd could be a valuable treatment option for patients with TROP2-expressing tumors in the clinical setting.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Delivery Systems/methods , Immunoconjugates/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Humans , Immunoconjugates/pharmacology , Macaca fascicularis , Male , Mice , Mice, Nude , RatsABSTRACT
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD). Here, we report the design, synthesis and structure-activity relationships (SAR) of a series of 4,6-disubstituted indazole compounds as hepcidin production inhibitors. The optimization study of multi-kinase inhibitor 1 led to the design of a potent and bioavailable hepcidin production inhibitor, 32 (DS28120313), which showed serum hepcidin-lowering effects in an interleukin-6-induced acute inflammatory mouse model.
Subject(s)
Acute Lung Injury/drug therapy , Drug Discovery , Hepcidins/antagonists & inhibitors , Indazoles/pharmacology , Inflammation/drug therapy , Pyrazoles/pharmacology , Acute Lung Injury/chemically induced , Administration, Oral , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Hep G2 Cells , Hepcidins/biosynthesis , Humans , Indazoles/administration & dosage , Indazoles/chemistry , Inflammation/chemically induced , Interleukin-6 , Mice , Molecular Structure , Pyrazoles/administration & dosage , Pyrazoles/chemistry , Structure-Activity RelationshipABSTRACT
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
Subject(s)
Benzoxazoles/chemistry , Benzoxazoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Hepcidins/antagonists & inhibitors , Administration, Oral , Animals , Benzoxazoles/administration & dosage , Benzoxazoles/pharmacokinetics , Carbamates/administration & dosage , Carbamates/pharmacokinetics , Gene Expression Regulation/drug effects , Half-Life , Hepcidins/genetics , Hepcidins/metabolism , Inflammation/chemically induced , Inflammation/drug therapy , Inhibitory Concentration 50 , Interleukin-6 , Maleates/administration & dosage , Maleates/chemistry , Maleates/pharmacokinetics , Maleates/pharmacology , Mice , Mice, Inbred C57BL , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Models, Animal , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , RNA, Messenger/metabolism , Structure-Activity RelationshipABSTRACT
Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of indazole compounds as hepcidin production inhibitors. The optimization study of compound 1 led to a potent hepcidin production inhibitor 45, which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.
Subject(s)
Anti-Infective Agents/chemical synthesis , Hepcidins/antagonists & inhibitors , Indazoles/chemistry , Anemia/drug therapy , Anemia/etiology , Animals , Anti-Infective Agents/pharmacokinetics , Anti-Infective Agents/therapeutic use , Chronic Disease , Half-Life , Hepcidins/blood , Hepcidins/metabolism , Indazoles/pharmacokinetics , Indazoles/therapeutic use , Inhibitory Concentration 50 , Interleukin-6/toxicity , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Structure-Activity RelationshipABSTRACT
To develop a novel and effective anticoagulant with potent and selective factor Xa (FXa) inhibitory activity, a new series of cinnamyl derivatives with enhanced lipophilicity and prodrug forms were synthesized and their biological activities were evaluated. As a result, we found that cinnamyl derivative (N-[4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl]-N-[(Z)-3-(3-amidinophenyl)-2-fluoro-2-propenyl]sulfamoyl)acetic acid dihydrochloride (26d, R-142086) with a fluorine atom on the double bond exhibited potent anticoagulant activity and no mutagenic potential. Moreover, orally administered R-142086 exhibited potent anti-FXa activity and anticoagulant activity in dogs.
Subject(s)
Amidines , Anticoagulants , Antithrombin III , Cinnamates/chemistry , Factor Xa Inhibitors , Sulfonamides , Administration, Oral , Amidines/chemical synthesis , Amidines/chemistry , Amidines/pharmacology , Animals , Anticoagulants/chemical synthesis , Anticoagulants/chemistry , Anticoagulants/pharmacology , Antithrombin III/chemical synthesis , Antithrombin III/chemistry , Antithrombin III/pharmacology , Cricetinae , Dogs , Humans , Male , Molecular Structure , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
To develop a potent and oral anticoagulant, a series of compounds with cinnamyl moiety was synthesized and their factor Xa (FXa) inhibitory activities were examined. As a result, some cinnamyl derivatives showed potent FXa inhibitory activities in vitro. Among them, compounds with substituent at the 3-position on the central benzene ring represented by (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-chlorophenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45b) and (N-{4-[1-(acetimidoyl)piperidin-4-yloxy]-3-carbamoylphenyl}-N-[(E)-3-(3-amidinophenyl)-2-propenyl]sulfamoyl)acetic acid dihydrochloride (45j) exhibited potent FXa inhibitory activities with IC(50) values of less than 10 nM in vitro. These compounds also showed potent anticoagulant activities both in vitro and ex vivo. Furthermore, these compounds exhibited no lethal toxicity (30 mg/kg, i.v.).
Subject(s)
Cinnamates/chemical synthesis , Cinnamates/pharmacology , Factor Xa Inhibitors , Animals , Blood Coagulation/drug effects , Cricetinae , Humans , In Vitro Techniques , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Trypsin Inhibitors/pharmacologyABSTRACT
A series of cinnamylindoline derivatives were synthesized, and their factor Xa (FXa) inhibitory activities and selectivity over trypsin were evaluated. Among them, some novel derivatives showed potent FXa inhibitory activities and good selectivity over trypsin. Especially, (E)-2-{5-[1-(acetimidoyl)piperidin-4-yloxy]-2-[2-(5-amidino-2-hydroxyphenyl)ethen-1-yl]indolin-1-ylsulfonyl}acetic acid (22f) having 2-hydroxycinnamyl moiety exhibited the most potent FXa inhibitory activity in vitro. Furthermore, 22f also exhibited potent anticoagulant activities in vitro.
Subject(s)
Anticoagulants/pharmacology , Cinnamates/pharmacology , Factor Xa Inhibitors , Indoles/pharmacology , Anticoagulants/chemical synthesis , Cinnamates/chemical synthesis , Cinnamates/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Inhibitory Concentration 50 , Magnetic Resonance Spectroscopy , Models, Chemical , Structure-Activity Relationship , Trypsin/metabolismABSTRACT
Factor Xa (FXa) is well known to play a pivotal role in blood coagulation, so FXa inhibitor is a promising drug candidate for prophylaxis and treatment of thromboembolic diseases. In the course of our research, we have found that (R)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)-1-(ethanesulfonyl)indoline ((R)-1) showed potent FXa inhibitory activity in vitro. However, single oral administation (RS)-1 showed high toxicity in mice. Among newly synthesized compounds, ({(RS)-5-[1-(acetimidoyl)piperidin-4-yloxy]-2-(7-amidinonaphthalen-2-yl)indolin-1-yl}sulfonyl)acetic acid ((RS)-11d) showed more potent FXa inhibitory activity and higher safety than (RS)-1. The R-isoform of compound 11d ((R)-11d) exhibited potent in vitro anticoagulant activity in human and hamster plasma. Orally administered (R)-11d also showed dose-dependent potent anticoagulant activity in hamsters, marmosets and cynomolgus monkeys. Compound (R)-11d with potent anticoagulant activity and high safety is therefore favorable as a novel oral FXa inhibitor.
Subject(s)
Anticoagulants/chemical synthesis , Anticoagulants/pharmacology , Factor Xa Inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Animals , Callithrix , Cricetinae , Dose-Response Relationship, Drug , Humans , Macaca fascicularis , Mice , Molecular StructureABSTRACT
A series of bisamidine derivatives each having a ring structure in the center of the molecule was synthesized and their Factor Xa (FXa) inhibitory activities were evaluated. Among them, some indoline derivatives showed potent inhibitory activities in vitro. In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a. Furthermore, (R)-18a exhibited more potent anticoagulant activity than DX-9065a. We also succeeded in obtaining an X-ray crystal structure of FXa bound with (R)-18a.
