Adriforant is a functional antagonist of histamine receptor 4 and attenuates itch and skin inflammation in mice

Uluçkan, Özge; Bruno, Sandro; Wang, Yichen; Wack, Nathalie; Wilzopolski, Jenny; Goetschy, Jean-François; Delucis-Bronn, Corinne; Urban, Beatrice; Fehlmann, Dominique; Stark, Holger; Hauchard, Alice; Roussel, E.; Kempf, Dominique; Kaupmann, Klemens; Raulf, Friedrich; Bäumer, Wolfgang; Röhn, Till A.; Zerwes, Hans Günter

doi:10.1016/j.ejphar.2023.175533

Cited by 5 publications

(3 citation statements)

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“…Two enantiomeric complementary IREDs were identified for the synthesis of (3R,4R)-and (3S,4S)-1-benzyl-4-dimethylpiperidin-3-amine, with high separation yield (83% and 91%), excellent stereoselectivity (97% and >99% ee) and diastereoselectivity (>99:1 dr), respectively, providing a green method for the production of key intermediates of Tofacitinib. 62 In 2022, researchers at Novartis developed a biosynthesis strategy of ZPL389 (H4 receptor antagonist) 63 catalyzed by the IR88 variant. 64 This enzyme catalytic pathway takes a large volume of pyrrolidone as substrate, and directly undergoes reductive amination with methylamine to obtain the catalytic product with up to 98% ee, and after being resolved by L-tartaric acid, the ee value of the product can reach 99%.…”

Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

“…In 2022, researchers at Novartis developed a biosynthesis strategy of ZPL389 (H4 receptor antagonist) catalyzed by the IR88 variant . This enzyme catalytic pathway takes a large volume of pyrrolidone as substrate, and directly undergoes reductive amination with methylamine to obtain the catalytic product with up to 98% ee, and after being resolved by l -tartaric acid, the ee value of the product can reach 99%.…”

Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

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Application of Imine Reductase in Bioactive Chiral Amine Synthesis

Wang,

Gao,

Gao

et al. 2024

Org. Process Res. Dev.

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Nitrogen-containing compounds, especially those with chiral amine structures, play a pivotal role in the field of organic active pharmaceutical ingredients. Traditional racemate resolution and chemical synthesis methods for the preparation of chiral amines suffer drawbacks such as high cost and environmental pollution. Over the past decades, stereoselective synthesis of nitrogen-containing compounds by biocatalytic methods such as imine reductase (IRED)-mediated transformation has become increasingly prominent. The prominence of imine reductases lies in their capacity to catalyze the reductive amination of aldehydes or ketones with primary or secondary amines, as well as their broader substrate scope. Furthermore, imine reductases exhibit diverse catalytic cycling systems that are unaffected by adverse reaction equilibria. This article focuses on the development of drug molecules or intermediates in biocatalytic synthesis mediated by imine reductase.

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Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

Section: Ired-mediated Synthesis Of Representative Drugsmentioning

confidence: 99%

Application of Imine Reductase in Bioactive Chiral Amine Synthesis

Wang,

Gao,

Gao

et al. 2024

Org. Process Res. Dev.

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“…Previous studies have shown that H4R activation regulates the phosphorylation of ERK in mast cells 10,11 . Recently, H4R was also reported to be co‐labelled with NeuN, a neuron maker, in the mouse spinal cord and DRG and involved in the regulation of chronic pain, itch and skin inflammation 12,13 . Whether H4R and p‐ERK in the spinal cord are involved in dry skin itch has not been investigated.…”

Section: Introductionmentioning

confidence: 99%

Spinal histamine H4 receptor mediates chronic pruritus via p‐ERK in acetone–ether–water (AEW)‐induced dry skin mice

Wang,

Li,

et al. 2024

Experimental Dermatology

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Dry skin is common to many pruritic diseases and is difficult to improve with oral traditional antihistamines. Recently, increasing evidence indicated that histamine H4 receptor (H4R) plays an important role in the occurrence and development of pruritus. Extracellular signal‐regulated kinase (ERK) phosphorylation activation in the spinal cord mediates histamine‐induced acute and choric itch. However, whether the histamine H4 receptor regulates ERK activation in the dry skin itch remains unclear. In the study, we explore the role of the histamine H4 receptor and p‐ERK in the spinal cord in a dry skin mouse model induced by acetone–ether–water (AEW). q‐PCR, Western blot, pharmacology and immunofluorescence were applied in the study. We established a dry skin itch model by repeated application of AEW on the nape of neck in mice. The AEW mice showed typically dry skin histological change and persistent spontaneous scratching behaviour. Histamine H4 receptor, instead of histamine H1 receptor, mediated spontaneous scratching behaviour in AEW mice. Moreover, c‐Fos and p‐ERK expression in the spinal cord neurons were increased and co‐labelled with GRPR‐positive neurons in AEW mice. Furthermore, H4R agonist 4‐methyhistamine dihydrochloride (4‐MH)induced itch. Both 4‐MH‐induced itch and the spontaneous itch in AEW mice were blocked by p‐ERK inhibitor U0126. Finally, intrathecal H4R receptor antagonist JNJ7777120 inhibited spinal p‐ERK expression in AEW mice. Our results indicated that spinal H4R mediates itch via ERK activation in the AEW‐induced dry skin mice.

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