RT Journal Article SR Electronic T1 Pharmacological screening identifies SHK242 and SHK277 as novel arginase inhibitors with efficacy against allergen-induced airway narrowing in vitro and in vivo JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.119.264341 DO 10.1124/jpet.119.264341 A1 Mariska P.M. Van den Berg A1 Santosh H. Kurhade A1 Harm Maarsingh A1 Stefanie Erceg A1 Imke R. Hulsbeek A1 Pieter H. Boekema A1 Loes E.M. Kistemaker A1 Martijn van Faassen A1 Ido P. Kema A1 Philip H. Elsinga A1 Alex S.S. Dömling A1 Herman Meurs A1 Reinoud Gosens YR 2020 UL http://jpet.aspetjournals.org/content/early/2020/04/08/jpet.119.264341.abstract AB AArginase is a potential target for asthma treatment. However, currently there are no arginase inhibitors available for clinical use. Here a novel class of arginase inhibitors was synthesized and their efficacy was pharmacologically evaluated. The reference compound 2(S)-amino-6-boronohexanoic acid (ABH) and a series of>200 novel arginase inhibitors were tested for their ability to inhibit recombinant human arginase 1 and 2 in vitro. The most promising compound were separated as enantiomers. Enantiomer-pairs SHK242 and SHK243, and SHK277 and SHK278 were tested Ffor functional efficacy by measuring, their effect on allergen-induced airway narrowing in lung slices of ovalbumin-sensitized guinea pigs was measured ex vivo. A guinea pig model of acute allergic asthma was used to examine the effect of the novel most efficacious enantiopure arginase inhibitors on allergen-induced airway hyperresponsiveness (AHR), early and late asthmatic reactions (EAR and LAR) and airway inflammation in vivo. The novel compounds were efficacious in inhibiting arginase 1 and 2 in vitro. The enantiopure SHK242 and SHK277 fully inhibited arginase activity with IC50-values of 3.4 and 10.5 μM for arginase 1, and 2.9 and 4.0 µM for arginase 2, respectively. Treatment of slices with ABH or novel compounds resulted in decreased ovalbumin-induced airway narrowing compared to control, explained by increased local nitric oxide production in the airway. In vivo, ABH, SHK242 and SHK277 protected against allergen-induced EAR and LAR, but not against AHR or lung inflammation. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions.SIGNIFICANCE STATEMENT Arginase is a potential drug target for asthma treatment, but currently there are no arginase inhibitors available for clinical use. We have identified promising novel arginase inhibitors for the potential treatment of allergic asthma that were able to protect against allergen-induced early and late asthmatic reactions. Our new inhibitors show protective effects in reducing airway narrowing in response to allergens and reductions in the early and late asthmatic response.