Identification of 4-benzylamino-2-[(4-morpholin-4-ylphenyl)amino]pyrimidine-5-carboxamide derivatives as potent and orally bioavailable STAT6 inhibitors.

Signal transducers and activators of transcription 6 (STAT6) is a key regulator of the type 2 helper T (Th2) cell immune response and a potential therapeutic target for allergic diseases such as asthma and atopic diseases. To search for potent and orally bioavailable STAT6 inhibitors, we synthesized a series of 4-benzylaminopyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 2-[(4-morpholin-4-ylphenyl)amino]-4-[(2,3,6-trifluorobenzyl)amino]pyrimidine-5-carboxamide (25y, YM-341619, AS1617612) showed potent STAT6 inhibition with an IC(50) of 0.70nM, and also inhibited Th2 differentiation in mouse spleen T cells induced by interleukin (IL)-4 with an IC(50) of 0.28 nM without affecting type 1 helper T (Th1) cell differentiation induced by IL-12. In addition, compound 25y showed an oral bioavailability of 25% in mouse.

[A case of pancreatic ductal adenocarcinoma with rapid progress in a young man].

A 17-year-old man was admitted to hospital because of epigastric pain. Various imaging studies showed a solid tumor (4cm in diameter) in the tail of the pancreas, multiple hypovascular tumors in liver. Serum levels of DUPAN2, SPAN1 and NSE were elevated slightly. Biopsy of hepatic tumor demonstrated that tumor cells had eosinophilic cytoplasm generally and unevenly distributed polymorphic nucleus. These data suggested that this tumor is poorly differentiated pancreatic carcinoma originated from the epithelium. Therefore, we administered 5-fluorouracil and cisplatin, combined with gemcitabine. The clinical status improved temporarily by the treatment, however, worsened rapidly. He died 81days after the treatment. Final diagnosis of autopsy was pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma in the young patients is rare, and we reported this case in addition to consideration on literature.

Familial occurrence of autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis in a mother and her daughter.

We encountered two patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family. A 68-year-old woman presented at our hospital from a previous medical institution because of the diagnosis of primary biliary cholangitis. Her 49-year-old daughter was admitted with liver dysfunction 4 years later. When compared, these two related patients were found to have overlapping features of primary biliary cholangitis and autoimmune hepatitis. Their human leukocyte antigen haplotype was DRB1*04:05/DRB1*15:02. The clinical and biochemical findings of these two patients immediately improved following treatment with a combination of prednisolone and ursodeoxycholic acid, in accordance with the Japanese guidelines. It is extremely important to identify such pathological conditions as quickly as possible, particularly with the appearance of severe liver dysfunction due to liver cirrhosis, as observed in our case. The Japanese guidelines are considered to be a realistic and useful clinical policy for the swift and efficient treatment of patients with overlapping features of primary biliary cholangitis and autoimmune hepatitis. We suggest that our two patients presented with a genetic predisposition to autoimmune liver disease with overlapping features of primary biliary cholangitis and autoimmune hepatitis within the same family.

[A case of recurrent early gastric cancer with peritonitis carcinomatosa successfully treated with TS-1].

A 62-year-old man with carcinomatous ascites more than 5 years after early gastric cancer operation was admitted to our hospital because of suspected pancreatic cancer, and was diagnosed with a relapse of the gastric cancer. TS-1 was administered at a dose of 120 mg/day. At the end of 1 course a partial response of a decrease of tumor markers and ascites and improvement of QOL was achieved, and the patient was followed in the outpatient clinic. The current case suggests that TS-1 may have a potent therapeutic efficacy in cases of gastric cancer relapse with carcinomatous ascites.

[A case of advanced gastric cancer successfully treated with TS-1].

A patient with advanced gastric cancer complicated with liver and lymph node metastases was successfully treated with a novel oral anticancer drug, TS-1, TS-1 was administered at a dose of 100 mg/day. One course consisted of consecutive administration of TS-1 for 28 days and withdrawal for 14 days. At the end of 3 courses a partial response of the liver metastases was achieved. Although the patient has had complications with ascites collection due to hypoalbuminemia, he has been well without regrowth of any metastases for over 8 months.

Synthesis and evaluation of 2-{[2-(4-hydroxyphenyl)-ethyl]amino}pyrimidine-5-carboxamide derivatives as novel STAT6 inhibitors.

The STAT6 (signal transducers and activators of transcription 6) protein is activated by interleukin (IL)-4 and IL-13, and plays an important role in T-helper cell 2 (Th2) differentiation. STAT6 might therefore be an excellent therapeutic target for various allergic conditions, including asthma and atopic diseases. We synthesized a series of 2-{[2-(4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide derivatives and evaluated their STAT6 inhibitory activities. Among these compounds, 4-(benzylamino)-2-{[2-(3-chloro-4-hydroxyphenyl)ethyl]amino}pyrimidine-5-carboxamide (2t, AS1517499) showed potent STAT6 inhibition with an IC(50) value of 21 nM, and also inhibited IL-4-induced Th2 differentiation of mouse spleen T cells with an IC(50) value of 2.3 nM and without influencing T-helper cell 1 (Th1) differentiation induced by IL-12.

A novel dual antagonist of thromboxane A2 and leukotriene D4 receptors: synthesis and structure-activity relationships of chloroquinolylvinyl derivatives.

To discover an orally active thromboxane A(2) (TXA(2)) and leukotriene D(4) (LTD(4)) dual antagonist, we designed and synthesized chloroquinolylvinyl derivatives based on the structures of the TXA(2) antagonist daltroban and the LTD(4) antagonist montelukast. Among these derivatives, 4-{[(2-(4-chlorophenylsulfonylamino)-1-{3-[(E)-2-(7-chloro-2-quinolyl)vinyl]phenyl}ethyl)thio]methyl}benzoic acid (18d) showed potent inhibitory activity against U46619-induced aggregation of guinea pig platelets and LTD(4)-induced contraction in the guinea pig ileum, with IC(50) values of 340 nm and 0.40 nm, respectively. Oral administration of 18 d also inhibited both the LTD(4)-induced acceleration of plasma leakage to skin in guinea pig and the U46619-induced increase in airway resistance in guinea pig with ED(50) values of 0.47 mg/kg and 3.3 mg/kg, respectively.