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Mechanisims of asthma and allergic disease – 1094. Pre-clinical characterization of RP3133, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders

Authors
Journal
World Allergy Organization Journal
1939-4551
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Volume
6
Identifiers
DOI: 10.1186/1939-4551-6-s1-p90
Keywords
  • Meeting Abstract
Disciplines
  • Medicine

Abstract

Mechanisims of asthma and allergic disease – 1094. Pre-clinical characterization of RP3133, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders MEETING ABSTRACT Open Access Mechanisims of asthma and allergic disease – 1094. Pre-clinical characterization of RP3133, a novel and potent CRAC channel inhibitor for the treatment of respiratory disorders Kasi Viswanath Routhu*, Sridhar Veeraraghavan, Gayatri Swaroop Merikapudi, Babu G, Srikant Viswanadha, Swaroop Vakkalanka From 2nd WAO International Scientific Conference (WISC 2012) Hyderabad, India. 6-9 December 2012 Introduction Calcium release activated calcium channels inhibitors have a potent role in treatment of autoimmune disor- ders mediated dysregulated T-lymphocyte and mast cell functioning. Herein, we describe the pre-clinical of RP3133, a novel and potent CRAC channel inhibitor with scope for development as a clinical candidate for asthma. Methods Inhibition of CRAC channel activity in Jurkat cells, cyto- kine release from human whole blood or PBMC, and mast cell degranulation were estimated. In vivo efficacy of the compound was determined in experimental mod- els of asthma in guinea pigs including PAF or ovalbu- min induced eosinophil infiltration into lungs ovalbumin induced histamine release from mast cells, and airway hyper-responsiveness. Results RP3133 significantly inhibited calcium entry into Jurkat cells (38 nM) besides reducing IL-4 (<550 nM) and IL- 5 (<750 nM) release from human whole blood and PBMC. Additionally, the compound suppressed IgE- induced mast cell degranulation at nanomolar concen- trations (139 nM). Oral administration of RP3133 in gui- nea pigs resulted in a dramatic reduction in eosinophil infiltration in an acute model of PAF-induced allergic asthma (ED50 = 0.2 mg/kg/p.o) as well as in an experi- mental model of ovalbumin-induced chronic airway inflammation (ED50 = 2.5 mg/kg/p.o). Additionally, RP3133 caused a significant reduction (P<0.05) citric acid, his

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