The world's first topical JAK inhibitor for treating "hand eczema" – Delgocitinib cream

2026-07-14 0 Leave me a message

Parameters

CAS	1263774-59-9
Molecular Formula	C₁₆H₁₈N₆O
Molecular Weight	310.35
Density	1.41±0.1 g/cm³
pKa	-0.65±0.40
Storage Condition	Store at -20 ℃

Introduction

Delgocitinib cream is an innovative, non-steroidal, topical pan-Janus kinase (JAK) inhibitor indicated for adults with chronic hepatitis E (CHE).

This drug specifically inhibits the activity of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2) by blocking the JAK-STAT signaling pathway, thereby suppressing various inflammatory responses that play a pivotal role in the pathogenesis and subsequent exacerbations of chronic hepatitis E (CHE).

Previously, delgocitinib has been approved in the European Union, the United Kingdom, Switzerland, and the UAE for the treatment of moderate-to-severe chronic exophthalmos (CHE) and is available in countries including Germany, Switzerland, the UK, and the UAE.

Synthetic Route

Bromolactone 128 reacts with benzylamine via an SN2 reaction to form α-amino lactone 129. Aminolactone 129 is then acylated with optically pure acyl chloride 131 (prepared by treatment with commercial acid 130 and sulfonyl chloride) to yield lactone 132. Lactone 132 is treated with LHMDS to generate an enol anion. This enol anion undergoes an SN2 substitution reaction to remove the chlorine atom, forming spirolactone 133 with a diastereoselectivity of 98:2 and enantioselectivity of 96%. The γ-carbon of spirolactone 133 is attacked by potassium phosphate anhydride, opening the lactone ring; the resulting carboxylic acid reacts with ethyl iodide to form an ethyl ester. Subsequently, treatment with diethylenetriamine releases the anhydride group, yielding a free amine that cyclizes via the corresponding ethyl ester intermediate to form spiroamide 134. The carbonyl group in spiroamide 134 is reduced using lithium aluminum hydride and aluminum chloride in tetrahydrofuran (THF) to obtain diamine 135, which is crystallized as succinate at a yield of 86%. Diamine 135 undergoes an SNAr reaction with chloropyrimidinopyrrole. The benzyl protecting group is removed via catalytic hydrogenation, yielding amine 137 overall with a total yield of 92%. Aminolactone 137 is then amidated with cyanoacetapyrazole. The resulting product is recrystallized in n-butanol with addition of 3 wt% BHT (butyl hydroxytoluene) as an antioxidant, yielding the final product digotinib at 86% yield, with both enantiomeric purity (ee) and diastereoselectivity (de) exceeding 99%.

Therapeutic efficacy

The FDA approval was based on two randomized, double-blind, placebo-controlled clinical trials spanning 16 weeks (TRIAL 1 and TRIAL 2), which enrolled a total of 960 adult patients with moderate-to-severe chronic adrenal hyperaldosteronism (CHE) who exhibited poor response to or were ineligible for topical corticosteroids.

The primary efficacy endpoint was the proportion of patients who achieved investigator global assessment of successful treatment for chronic hand eczema (IGA-CHE) at week 16, defined as a score of 0 (complete clearance) or 1 (near-complete clearance) with an improvement of at least 2 points from baseline.

The results showed that in TRIAL 1 and TRIAL 2, 20% and 29% of patients in the delgocitinib group achieved IGA-CHE TS, compared to 10% and 7% in the placebo group.

Furthermore, the delgocitinib group demonstrated significantly better improvements in pruritus and pain scores on the Hand Eczema Symptoms Diary (HESD) compared to the placebo group.

Security

Regarding safety, adverse reactions associated with delgocitinib include local reactions (such as pain, tingling, pruritus, and erythema), bacterial skin infections (e.g., finger cellulitis and paronychia), and leukopenia.

In clinical trials, the incidence of adverse events reported in the delgocitinib group was lower and comparable to that in the placebo group. The FDA recommends avoiding concomitant use of delgocitinib with other JAK inhibitors or potent immunosuppressants during treatment, and emphasizes the importance of monitoring infection risks and the occurrence of non-melanoma skin cancer.

Preparation Method of Cagrilintide

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