Delgocitinib Chemical Properties

Density 

1.41±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

DMSO:58.0(Max Conc. mg/mL);186.89(Max Conc. mM)

pka

-0.65±0.40(Predicted)

form 

Solid

color 

White to off-white

InChI

InChI=1S/C16H18N6O/c1-11-8-22(13(23)2-5-17)16(11)4-7-21(9-16)15-12-3-6-18-14(12)19-10-20-15/h3,6,10-11H,2,4,7-9H2,1H3,(H,18,19,20)/t11-,16-/m0/s1

InChIKey

LOWWYYZBZNSPDT-ZBEGNZNMSA-N

SMILES

N1(C(=O)CC#N)[C@]2(CCN(C3N=CN=C4NC=CC4=3)C2)[C@@H](C)C1

Delgocitinib Usage And Synthesis

Description

Delgocitinib is an inhibitor of JAK1, JAK2, JAK3, and tyrosine kinase 2 (TYK2; IC50s = 2.8, 2.6, 13, and 58 nM, respectively).1 It is selective for JAK1, JAK2, JAK3, and TYK2 over lymphocyte cell-specific tyrosine kinase (LCK; IC50 = 5,800 nM). Delgocitinib inhibits IL-31-induced increases in STAT3 phosphorylation levels in A549 cells (IC50 = 25 nM). It reduces IL-31-induced scratching in mice in a dose-dependent manner.2 Formulations containing delgocitinib have been used in the treatment of atopic dermatitis.WARNING This product is not for human or veterinary use.

Characteristics

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

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.

Pharmacokinetics

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.

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.

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.

Synthesis

Bromolactone 128 reacted with benzylamine via SN2 reaction to generate α-aminolactone 129, which was acylated with optically pure acid chloride 131 (prepared by treatment of commercial acid 130 with thionyl chloride) to give lactone 132. Lactone 132 was treated with LHMDS to generate the enolate anion. The enolate anion removed the chlorine atom via SN2 substitution to form spirolactone 133, with two stereogenic centers established in a 98:2 diastereomeric ratio (dr) and 96% enantiomeric purity. The γ-carbon of spirolactone 133 was attacked by potassium phosphoanhydride to open the lactone ring, and the resulting carboxylic acid was converted to the ethyl ester by reaction with ethyl iodide. Finally, treatment with diethylenetriamine liberated the anhydride group to provide a free amine, which cyclized via the corresponding ethyl ester intermediate to form spirolactam 134. The carbonyl group in spirolactam 134 was reduced using lithium aluminum hydride and aluminum chloride in tetrahydrofuran (THF) to give diamine 135, which was crystallized as a succinate salt in 86% yield. Diamine 135 was subjected to SNAr reaction with chloropyrimidopyrrole. The benzyl protecting group was removed by catalytic hydrogenation, and the amine 137 was obtained in 92% overall yield after these two steps. Amine 137 was amidated with cyanoacetylpyrazole. The product of the reaction of amine 137 with cyanoacetylpyrazole was recrystallized from n-butanol and 3 wt% BHT (butylated hydroxytoluene) was added as an antioxidant to give the final product, digaotinib, in 86% yield with enantiomeric purity (ee) and diastereomeric purity (de) greater than 99%.