ABSTRACT
ORAI1 constitutes the pore-forming subunit of the calcium release-activated calcium (CRAC) channel, which is responsible for store-operated calcium entry into lymphocytes. It is known that ORAI1 is essential for the activation of T cells and mast cells and is considered to be a potent therapeutic target for autoimmune and allergic diseases. Here, we obtained a new humanized antibody, DS-2741a, that inhibits ORAI1 function. DS-2741a bound to human-ORAI1 with high affinity and without cross-reactivity to rodent Orai1. DS-2741a demonstrated suppression of CRAC-mediated human and mouse T-cell activation and mast cell degranulation in human ORAI1 knock-in mice. Furthermore, DS-2741a ameliorated house dust mite antigen-induced dermatitis in the human ORAI1 knock-in mouse. Taken together, DS-2741a inhibited T-cell and mast cell functions, thus improving skin inflammation in animal models of atopic dermatitis and reinforcing the need for investigation of DS-2741a for the treatment of allergic diseases in a clinical setting.
ABSTRACT
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis. The inhibition of hepcidin may be a favorable strategy for the treatment of anemia of chronic disease. Here, we have reported the design, synthesis, and structure-activity relationships (SAR) of a series of 4-aminopyrimidine compounds as inhibitors of hepcidin production. The optimization study of 1 led to the design of a potent and bioavailable inhibitor of hepcidin production, 34 (DS42450411), which showed serum hepcidin-lowering effects in a mouse model of interleukin-6-induced acute inflammation.
Subject(s)
Aminopyridines/pharmacology , Anemia/drug therapy , Hepcidins/antagonists & inhibitors , Quinazolines/pharmacology , Administration, Oral , Aminopyridines/administration & dosage , Aminopyridines/chemical synthesis , Aminopyridines/pharmacokinetics , Anemia/etiology , Animals , Binding Sites , Cell Line, Tumor , Drug Design , Hepcidins/blood , Hepcidins/chemistry , Humans , Inflammation/chemically induced , Inflammation/complications , Interleukin-6/metabolism , Iron/metabolism , Male , Mice, Inbred C57BL , Molecular Structure , Quinazolines/administration & dosage , Quinazolines/chemical synthesis , Quinazolines/pharmacokinetics , Structure-Activity RelationshipABSTRACT
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
Psoriasis is a common inflammatory skin disease that affects approximately 1% of the population worldwide. Tumor necrosis factor-alpha-induced protein 3 (TNFAIP3) gene polymorphisms have been strongly associated with psoriasis susceptibility. In this study, we investigate how TNFAIP3, also known as A20, may regulate psoriasis susceptibility. We found that haplo-insufficient A20+/- mice develop severe toll-like receptor (TLR)-induced skin inflammation compared to wild type mice owing to amplified production of interleukin (IL)-17 and IL-23. Examination of TNFAIP3 mRNA expression in skin biopsies from patients with psoriasis revealed reduced expression in both involved and uninvolved skin. Our results demonstrate the clinical importance of reduced dermal expression of A20 in psoriasis and suggest that A20 restriction of the IL-23/17 axis protects against psoriasis.
