Renoprotective effects of laxative linaclotide: Inhibition of acute kidney injury and fibrosis in a rat model of renal ischemia-reperfusion.

Ischemia-reperfusion (I/R) leads to tissue damage in transplanted kidneys, resulting in acute kidney injury (AKI) and chronic graft dysfunction, which critically compromises transplant outcomes, such as graft loss. Linaclotide, a guanylate cyclase C agonist clinically approved as a laxative, has recently been identified to exhibit renoprotective effects in a chronic kidney disease (CKD) model. This study evaluates the therapeutic effects of linaclotide on AKI triggered by I/R in a rat model with an initial comparison with other laxatives. Here, we show that linaclotide administration resulted in substantial reduction in serum creatinine levels, reflective of enhanced renal function. Histological examination revealed diminished tubular damage, and Sirius Red staining confirmed less collagen deposition, collectively indicating preserved structural integrity and mitigation of fibrosis. Further analysis demonstrated lowered expression of TGF-ß and associated fibrotic markers, α-SMA, MMP2, and TIMP1, implicating the downregulation of the fibrogenic TGF-ß pathway by linaclotide. Furthermore, one day after I/R insult, linaclotide profoundly diminished macrophage infiltration and suppressed critical pro-inflammatory cytokines such as TNF, IL-1ß, and IL-6, signifying its potential to disrupt initial inflammatory mechanisms integral to AKI pathology. These findings suggest that linaclotide, with its established safety profile, could extend its benefits beyond gastrointestinal issues and potentially serve as a therapeutic intervention for organ transplantation. Additionally, it could provide immediate and practical insights into selecting laxatives for managing patients with AKI or CKD, regardless of the cause, and for those receiving dialysis or transplant therapy.

Discovery of novel pyrrole derivatives as potent agonists for the niacin receptor GPR109A.

Novel pyrrole derivatives were discovered as potent agonists of the niacin receptor, GPR109A. During the derivatization, compound 16 was found to be effective both in vitro and in vivo. The compound 16 exhibited a significant reduction of the non-esterified fatty acid in human GPR109A transgenic rats, and the duration of its in vivo efficacy was much longer than niacin.

Discovery of novel pyridazine derivatives as glucose transporter type 4 (GLUT4) translocation activators.

We report herein the synthesis and structure-activity relationships (SAR) of a series of pyridazine derivatives with the activation of glucose transporter type 4 (GLUT4) translocation. Through a cell-based phenotype screening in L6-GLUT4-myc myoblasts and functional glucose uptake assays, lead compound 1a was identified as a functional small molecule. After further derivatization, the thienopyridazine scaffold as the central ring (B-part) was revealed to have potent GLUT4 translocation activities. Consequently, we obtained promising compound 26b, which showed a significant blood glucose lowering effect in the severe diabetic mice model (10-week aged db/db mice) after oral dosing even at 10 mg/kg, implying that our pyridazine derivatives have potential to become novel therapeutic agents for diabetes mellitus.

Design, synthesis, and pharmacological evaluation of a novel series of hormone sensitive lipase inhibitor.

HSL inhibition is a promising approach to the treatment of dyslipidemia. As a result of re-optimization of lead compound 2, we identified novel compound 25a exhibiting potent inhibitory activity against HSL enzyme and cell with high selectivity for cholinesterases (AChE and BuChE). Reflecting its potent in vitro activity, compound 25a exhibited antilipolytic effect in rats at 1mg/kg p.o., which indicated that this novel compound is the most potent orally active HSL inhibitor. Moreover, compound 25a did not show bioactivation liability.

Identification of a novel hormone sensitive lipase inhibitor with a reduced potential of reactive metabolites formation.

Hormone sensitive lipase (HSL) has emerged as an attractive target for the treatment of dyslipidemia. We previously reported compound 1 as a potent and orally active HSL inhibitor. Although an attractive profile was demonstrated, subsequent studies revealed that compound 1 has a bioactivation liability. The oxygen-carbon linker in compound 1 was identified as being potentially responsible for reactive metabolite formation. By exchanging of this susceptible fragment was feasible, and a benzanilide derivative 6b with a decreased bioactivation liability was obtained. Further modification of the novel benzanilide scaffold resulted in the identification of compound 24b. Compound 24b exhibited potent HSL inhibitory activity (IC50=2nM) with a significantly reduced bioactivation potential. Oral administration of compound 24b exhibited an antilipolytic effect on rats at 3mg/kg.

Identification of a novel boronic acid as a potent, selective, and orally active hormone sensitive lipase inhibitor.

Hormone sensitive lipase (HSL) is an attractive therapeutic target of dyslipidemia. We designed and synthesized several compounds as reversible HSL inhibitors with a focus on hydrophobic interactions, which was thought to be effective upon the HSL inhibitory activity. In these efforts, we identified boronated compound 12 showing a potent HSL inhibitory activity with an IC50 value of 7nM and a high selectivity against cholinesterases. Furthermore, compound 12 is the first boron containing HSL inhibitor that has shown an antilipolytic effect in rats after oral administration at 3mg/kg.

Synthesis and Structure-Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists.

We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.

Recurrent and progressive abdominal pain and enteritis in a Japanese patient with paroxysmal nocturnal hemoglobinuria.

This case report describes a young male patient with recurrent abdominal pain persisting for more than 16 months. Clinical investigations showed signs of inflammation and pancytopenia. A diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) was made 9 months after the onset of the abdominal pain, following endoscopic examinations that revealed evidence of a previously unknown hemorrhage. Regular monitoring indicated that the abdominal pain was associated with elevations in lactate dehydrogenase, C-reactive proteins, and D-dimer levels. The patient started treatment with the complement inhibitor eculizumab shortly after it was approved for use in Japanese PNH patients with hemolysis. Resolution of the abdominal pain and normalization of clinical parameters were noted within 3 weeks from treatment initiation.

Synthesis and structure-activity relationships of novel zwitterionic compounds as peroxisome proliferator activated receptor α/γ dual agonists with improved physicochemical properties.

We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.

Design, synthesis and evaluation of novel zwitterionic compounds as PPARα/γ dual agonists (1).

We describe here the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. We commenced the medicinal research with compound 1 originated by Eli Lilly, which was reported to possess PPAR α/γ dual agonist activity. We incorporated an amine linker and optimized it on the nitrogen of the linker, thereby envisioning the enhancement of the PPAR α/γ dual agonist activity together with altering the physicochemical properties. As a result, we could generate compounds showing the PPAR α/γ dual activity, especially among which compound 22e had a franylmethyl group on the linker and 2,6-dimethyl phenyl ring at the carboxylic acid head group furnishing a highly potent dual agonist activity, together with a great glucose lowering effect. Moreover, it remedied the lipid profile, that is, triglyceride without body weight gain in the db/db mice model.

[A case of pneumocystis pneumonia during chemotherapy for gastric cancer].

We report a death case of a man in his sixties with pneumocystis pneumonia during chemotherapy for gastric cancer. He was diagnosed with cStage IIIB (T4a, N2, H0, P0, M0). Because of bulky N2, systemic chemotherapy of S-1 and CDDP was performed from April 2009. But no reductions were noted after 2 courses. We next treated this patient with S-1 and CPT-11. He had also received corticosteroid treatment for nausea. Because of high fever and choke, he came to our hospital at day 12 in 3 courses, and a severe respiratory failure occurred. CT of the chest showed diffuse ground-glass bilateral opacities, and we immediately started a treatment with trimethoprim-sulfamethozazole and corticosteroid for the possibility of pneumocystis pneumonia. We finally deduced pneumocystis pneumonia from markedly elevated serum beta-D-glucan and PCR positive after hospitalization. In spite of early treatments, he died of bacterial pneumonia and gastric cancer. We should be careful of pneumocystis pneumonia during chemotherapy and corticosteroid treatment.

Discovery of N-[(1R,2S,5S)-2-{[(5-chloroindol-2-yl)carbonyl]amino}-5-(dimethylcarbamoyl)cyclohexyl]-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxamide hydrochloride: a novel, potent and orally active direct inhibitor of factor Xa.

In the early 1990's, we reported on the low-molecular selective fXa inhibitor DX-9065a having two amidino groups. However, it had poor oral bioavailability due to its strong basic amidino groups. To obtain fXa inhibitors with improved oral bioavailability, we investigated various non-amidino fXa inhibitors and finally discovered cis-1,2-diaminocyclohexane derivative 4c to have potent fXa inhibition, promising anticoagulant activity, and good oral bioavailability, compared with amidino compound DX-9065a. In addition, we will discuss the influence of the third substituent on the cyclohexane ring on anti-fXa activity, anticoagulant activity, PK profile, and lipophilicity.

[Successful treatment with imatinib mesylate for Philadelphia chromosome-positive refractory acute myeloid leukemia].

A 51-year-old man was diagnosed as having Philadelpha (Ph) chromosome-positive acute myeloid leukemia (AML) with major-BCR/ABL mRNA. He achieved complete remission after induction chemotherapy. Five months later, he was again positive for the Ph chromosome despite additional chemotherapy. He was therefore treated with imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, at a dose of 600 mg/day. However, the treatment was interrupted because of thrombocytopenia, skin eruption and face edema. After the patient recovered from these side effects, imatinib was readministered at a dose of 400 mg/day and a complete cytogenetic response was achieved. Imatinib is expected to be an effective drug for Ph chromosome-positive AML.