Departments of Molecular Pharmacology (M.P.M.v.d.B., S.E., I.R.H., P.H.B., L.E.M.K., H.Me., R.G.) and Drug Design (S.H.K., A.D.), Groningen Research Institute of Pharmacy, University of Groningen. Department of Laboratory Medicine, University Medical Center Groningen (M.v.F., I.P.K.), University of Groningen, Groningen, The Netherlands; Department of Pharmaceutical Sciences, Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, Florida (H.Ma.); and Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (P.H.E.).
Departments of Molecular Pharmacology (M.P.M.v.d.B., S.E., I.R.H., P.H.B., L.E.M.K., H.Me., R.G.) and Drug Design (S.H.K., A.D.), Groningen Research Institute of Pharmacy, University of Groningen. Department of Laboratory Medicine, University Medical Center Groningen (M.v.F., I.P.K.), University of Groningen, Groningen, The Netherlands; Department of Pharmaceutical Sciences, Lloyd L. Gregory School of Pharmacy, Palm Beach Atlantic University, West Palm Beach, Florida (H.Ma.); and Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands (P.H.E.)
J Pharmacol Exp Ther. 2020 Jul;374(1):62-73. doi: 10.1124/jpet.119.264341. Epub 2020 Apr 8.
Arginase is a potential target for asthma treatment. However, there are currently 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 >200 novel arginase inhibitors were tested for their ability to inhibit recombinant human arginase 1 and 2 in vitro. The most promising compounds were separated as enantiomers. Enantiomer pairs SHK242 and SHK243, and SHK277 and SHK278 were tested for functional efficacy by measuring their effect on allergen-induced airway narrowing in lung slices of ovalbumin-sensitized guinea pigs ex vivo. A guinea pig model of acute allergic asthma was used to examine the effect of the most efficacious enantiopure arginase inhibitors on allergen-induced airway hyper-responsiveness (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 IC 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 with 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.
精氨酸酶是治疗哮喘的潜在靶点。然而，目前尚无可用于临床的精氨酸酶抑制剂。在这里，我们合成了一类新型的精氨酸酶抑制剂，并对其药效进行了评估。参考化合物 2(S)-氨基-6-硼己酸（ABH）和 >200 种新型精氨酸酶抑制剂被测试其抑制重组人精氨酸酶 1 和 2 的体外能力。最有前途的化合物被分离为对映体。对映体对 SHK242 和 SHK243 以及 SHK277 和 SHK278 进行了功能功效测试，通过测量它们对卵清蛋白致敏豚鼠离体肺切片中变应原诱导的气道狭窄的影响。使用豚鼠急性变应性哮喘模型研究了最有效的手性纯精氨酸酶抑制剂对变应原诱导的气道高反应性（AHR）、早期和晚期哮喘反应（EAR 和 LAR）以及体内气道炎症的影响。新型化合物在体外有效抑制精氨酸酶 1 和 2。手性纯 SHK242 和 SHK277 完全抑制精氨酸酶活性，对精氨酸酶 1 和 2 的 IC 值分别为 3.4 和 10.5 μM，对精氨酸酶 2 的 IC 值分别为 2.9 和 4.0 μM。与对照相比，用 ABH 或新型化合物处理切片可导致卵清蛋白诱导的气道狭窄减少，这可以通过气道中局部一氧化氮产生的增加来解释。在体内，ABH、SHK242 和 SHK277 可预防变应原诱导的 EAR 和 LAR，但不能预防 AHR 或肺炎症。我们已经确定了有前途的新型精氨酸酶抑制剂，可用于治疗过敏性哮喘，这些抑制剂能够预防变应原诱导的早期和晚期哮喘反应。
