Delgocitinib

Characteristics

Class: non-receptor tyrosine kinase
Treatment: atopic dermatitis (topical ointment)
Protein binding = 22–29%

Definition

ChEBI: Delgocitinib is a pyrrolopyrimidine that is 7H-pyrrolo[2,3-d]pyrimidine substituted by a (3S,4R)-1-(cyanoacetyl)-3-methyl-1,6-diazaspiro[3.4]octan-6-yl group at position 4. It is a pan-Janus kinase (JAK) inhibitor and is approved for treatment of atopic dermatitis (AD) in Japan. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor, an anti-inflammatory drug, an antipsoriatic and an antiseborrheic. It is a pyrrolopyrimidine, a tertiary amino compound, a nitrile, an azaspiro compound, a tertiary carboxamide and a N-acylazetidine.

Definition

The lead compound to delgocitinib was tofacitinib, a potent pan-JAK inhibitor. To maintain the overall pan-JAK inhibition profile of tofacitinib, the pyrrolopyrimidine hinge binder, and the cyanoacetyl group were kept fixed. At the same time, the central aminopiperidine linker was replaced by a variety of spirocyclic scaffolds to maintain comparable binding patterns. This effort identified the three-dimensional diazaspiro[3.4]octane scaffold as the optimal linker, and further SAR studies led to delgocitinib, which demonstrates better selectivity against JAK3 compared to tofacitinib and its selectivity for the JAK family over LCK is also improved. Delgocitinib exhibits no significant inhibition of non-JAK kinases under 1 μM except ROCK2.

Definition

Delgocitinib is metabolically stable in both liver microsomes and hepatocytes across species (human, rat, dog, and monkey), and it is also not metabolized in human skin microsomes. It has favorable oral bioavailability in rats (78%) and dogs (124%). Following repeat topical application to the affected area twice daily with a maximum dose of 5 g per application, plasma levels of delgocitinib were detected in 12%, 16%, 14%, and 12% of the patients at week 4, 12, 28, and 52, respectively.

Clinical Use

Delgocitinib is a pan-JAK inhibitor that inhibits all Janus Kinase (JAK) family members. Topical delgocitinib 0.5% ointment received its first approval in Japan in 2020 for treating adults with atopic dermatitis. The FDA has granted delgocitinib cream fast-track designation for chronic hand eczema.