Discovery of CYR715: A novel carboxylic acid-containing soluble guanylate cyclase stimulator.

Soluble guanylate cyclase (sGC) is a clinically validated therapeutic target in the treatment of pulmonary hypertension. Modulators of sGC have the potential to treat diseases that are affected by dysregulation of the NO-sGC-cGMP signal transduction pathway. This letter describes the SAR efforts that led to the discovery of CYR715, a novel carboxylic acid-containing sGC stimulator, with an improved metabolic profile relative to our previously described stimulator, IWP-051. CYR715 addressed potential idiosyncratic drug toxicity (IDT) liabilities associated with the formation of reactive, migrating acyl glucuronides (AG) found in related carboxylic acid-containing analogs and demonstrated high oral bioavailability in rat and dose-dependent hemodynamic pharmacology in normotensive Sprague-Dawley rats.

[Combination Chemotherapy Using Sorafenib and Hepatic Arterial Infusion with a Fine-Powder Formulation of Cisplatin for Advanced Hepatocellular Carcinoma with Portal Vein Tumor Thrombosis--A Case Report].

Sorafenib has been a standard therapy for advanced hepatocellular carcinoma (HCC) with portal vein thrombosis. Hepatic arterial infusion chemotherapy (HAIC) is still preferably performed in Japan because of its relatively good tumor-shrinking effect. We report a case of advanced multiple HCC with portal thrombus that responded to combination chemotherapy with sorafenib and repeat hepatic arterial infusion with a fine-powder formulation of cisplatin (IA-call®). A 57-year-old man presented for the treatment of HCC with alcoholic cirrhosis. Multiple HCC were found to be rapidly progressing with portal thrombosis. HAIC with IA-call® was performed, but the tumors progressed. TAE was performed 3 times thereafter and the main tumor shrunk to some extent. A month after the last TAE, the HCC was found to progress again, and oral sorafenib was administered. A reservoir and catheter were placed and HAIC with low-dose 5-fluorouracil and cisplatin was performed for 3 cycles following 1 HAIC cycle with epirubicin and mitomycin C, which was not effective. For 10 months after initial therapy, HAIC using IA-call® has been performed once for 6 weeks. After performing HAIC with IA-call® 5 times, the serum levels of HCC tumor markers AFP and PIVKA-Ⅱdecreased, and the tumors continued to shrink and were not stained on enhanced CT scan. The patient has been alive for 23 months after the initial therapy and has maintained stable disease.

[Three cases of recurrent hepatocellular carcinoma treated with laparoscopic hepatectomy after oral administration of sorafenib].

Case 1 involved a 63-year-old woman who had multiple hepatocellular carcinomas (HCC) associated with hepatitis C virus infection. She was treated with hepatic arterial infusion chemotherapy (HAIC) and transcatheter arterial chemoembolization (TACE), followed by oral administration of sorafenib (200 mg/day). However, a lesion on the left lateral segment of the liver enlarged rapidly. Laparoscopic left lateral sectionectomy was performed. Histopathological examination revealed combined hepatocellular and cholangiocellular carcinoma. Case 2 involved a 54-year-old man who had multiple recurrent HCCs associated with hepatitis C virus infection after undergoing hepatectomy twice. Oral administration of sorafenib (200 mg/day) was initiated. The intrahepatic lesions decreased in size, but metastasis in an enlarged lymph node behind the portal vein was suspected. Laparoscopic partial hepatectomy and lymph node dissection were performed. HCC metastasis in the lymph node and partial necrosis in the intrahepatic lesions were identified histopathologically. Case 3 involved a 56- year-old man who had multiple recurrent HCCs associated with hepatitis C virus infection. TACE was performed thrice, and oral administration of sorafenib( 400-600 mg/day) was initiated. The lesion in the right lateral segment of the liver decreased in size but lesions in the left lateral segment were enlarged. Therefore, laparoscopic left hemihepatectomy was performed.