A dual antagonist for chemokine CCR3 receptor and histamine H1 receptor. 2007

Keiko Suzuki, and Tatsuaki Morokata, and Koichiro Morihira, and Ippei Sato, and Satoko Takizawa, and Masayuki Kaneko, and Koichiro Takahashi, and Yasuaki Shimizu
Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Osaka 532-8514, Japan. keiko-suzuki@jp.astellas.com

Eosinophilic chemokines and histamine play distinct but important roles in allergic diseases. Inhibition of both eosinophilic chemokines and histamine, therefore, is an ideal strategy for the treatment of allergic inflammation, such as asthma, allergic rhinitis, and atopic dermatitis. YM-344484 was found to potently inhibit both the CCL11-induced Ca2+ influx in human CCR3-expressing cells (Kb=1.8 nM) and histamine-induced Ca2+ influx in histamine H1 receptor-expressing PC3 cells (Kb=47 nM). YM-344484 also inhibited the CCL11-induced chemotaxis of human CCR3-expressing cells (IC50=6.2 nM) and CCL11-induced eosinophil-derived neurotoxin release from human eosinophils (IC50=19 nM). Orally administered YM-344484 inhibited the increase in histamine-induced vascular permeability in mice (82% inhibition at a dose of 10 mg/kg) and the accumulation of eosinophils in a mouse asthma model (74% at a dose of 300 mg/kg). These results indicate that YM-344484, a novel and functional dual antagonist for chemokine CCR3 receptor and histamine H1 receptor, is an attractive candidate for development as a novel anti-allergic inflammation drug.

UI MeSH Term Description Entries
D008807 Mice, Inbred BALB C An inbred strain of mouse that is widely used in IMMUNOLOGY studies and cancer research. BALB C Mice, Inbred,BALB C Mouse, Inbred,Inbred BALB C Mice,Inbred BALB C Mouse,Mice, BALB C,Mouse, BALB C,Mouse, Inbred BALB C,BALB C Mice,BALB C Mouse
D010047 Ovalbumin An albumin obtained from the white of eggs. It is a member of the serpin superfamily. Serpin B14
D010880 Piperidines A family of hexahydropyridines.
D011014 Pneumonia Infection of the lung often accompanied by inflammation. Experimental Lung Inflammation,Lobar Pneumonia,Lung Inflammation,Pneumonia, Lobar,Pneumonitis,Pulmonary Inflammation,Experimental Lung Inflammations,Inflammation, Experimental Lung,Inflammation, Lung,Inflammation, Pulmonary,Inflammations, Lung,Inflammations, Pulmonary,Lobar Pneumonias,Lung Inflammation, Experimental,Lung Inflammations,Lung Inflammations, Experimental,Pneumonias,Pneumonias, Lobar,Pneumonitides,Pulmonary Inflammations
D011657 Pulmonary Eosinophilia A condition characterized by infiltration of the lung with EOSINOPHILS due to inflammation or other disease processes. Major eosinophilic lung diseases are the eosinophilic pneumonias caused by infections, allergens, or toxic agents. Eosinophilia, Pulmonary,Eosinophilic Pneumonia,Loeffler Syndrome,Pneumonia, Eosinophilic,Eosinophilias, Pulmonary,Pulmonary Eosinophilias,Simple Pulmonary Eosinophilia,Tropical Eosinophilic Pneumonia,Eosinophilic Pneumonia, Tropical,Eosinophilic Pneumonias,Eosinophilic Pneumonias, Tropical,Pneumonias, Eosinophilic,Pulmonary Eosinophilia, Simple,Simple Pulmonary Eosinophilias,Syndrome, Loeffler,Tropical Eosinophilic Pneumonias
D011724 Pyridazines Six-membered rings with two adjacent nitrogen atoms also called 1,2-diazine.
D011969 Receptors, Histamine H1 A class of histamine receptors discriminated by their pharmacology and mode of action. Most histamine H1 receptors operate through the inositol phosphate/diacylglycerol second messenger system. Among the many responses mediated by these receptors are smooth muscle contraction, increased vascular permeability, hormone release, and cerebral glyconeogenesis. (From Biochem Soc Trans 1992 Feb;20(1):122-5) H1 Receptor,Histamine H1 Receptors,H1 Receptors,Histamine H1 Receptor,Receptors, H1,H1 Receptor, Histamine,H1 Receptors, Histamine,Receptor, H1,Receptor, Histamine H1
D002199 Capillary Permeability The property of blood capillary ENDOTHELIUM that allows for the selective exchange of substances between the blood and surrounding tissues and through membranous barriers such as the BLOOD-AIR BARRIER; BLOOD-AQUEOUS BARRIER; BLOOD-BRAIN BARRIER; BLOOD-NERVE BARRIER; BLOOD-RETINAL BARRIER; and BLOOD-TESTIS BARRIER. Small lipid-soluble molecules such as carbon dioxide and oxygen move freely by diffusion. Water and water-soluble molecules cannot pass through the endothelial walls and are dependent on microscopic pores. These pores show narrow areas (TIGHT JUNCTIONS) which may limit large molecule movement. Microvascular Permeability,Permeability, Capillary,Permeability, Microvascular,Vascular Permeability,Capillary Permeabilities,Microvascular Permeabilities,Permeabilities, Capillary,Permeabilities, Microvascular,Permeabilities, Vascular,Permeability, Vascular,Vascular Permeabilities
D002633 Chemotaxis The movement of cells or organisms toward or away from a substance in response to its concentration gradient. Haptotaxis
D004195 Disease Models, Animal Naturally-occurring or experimentally-induced animal diseases with pathological processes analogous to human diseases. Animal Disease Model,Animal Disease Models,Disease Model, Animal

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