Neuropathy is a serious complication of diabetes that has a significant socioeconomic impact, since it frequently demands high levels of health care consumption and compromises labor productivity. Recently, LASSBio-1471 (3) was demonstrated to improve oral glucose tolerance, reduce blood glucose levels, and display an anti-neuropathy effect in a murine streptozotocin-induced diabetes model. In the present work, we describe the design, synthesis, solubility, plasma stability, and pharmacological evaluation of novel sulfonylhydrazone derivatives (referred to herein as compounds 4–9), which were designed by molecular modification based on the structure of the prototype LASSBio-1471 (3). Among the compounds tested, better plasma stability was observed with 4, 5, and 9 in comparison to compounds 6, 7, and 8. LASSBio-1773 (7), promoted not only hypoglycemic activity but also the reduction of thermal hyperalgesia and mechanical allodynia in a murine model of streptozotocin-induced diabetic neuropathic pain.

This work describes a novel ligand for peroxisome proliferator-activated receptor gamma (PPARgamma) and its hypoglycemic and analgesic activity in a murine model of diabetes-induced neuropathic pain. The molecular recognition of LASSBio-1772 by a PPARgamma binding domain showed that the compound is a partial agonist. Four weeks after male Wistar rats received a single intravenous injection of streptozotocin (STZ, 60 mg/kg), plasma glucose levels were increased from 92.5 ± 3.7 to 465.0 ± 21.6 mg/dL (P < 0.01) and serum insulin was reduced from 66.8 ± 7.8 to 25.5 ± 5.6 pmol/L (P<0.01). Diabetic animals were then, treated with either vehicle or LASSBio-1772 (50 mg/kg, i.p.) daily for 7 days. LASSBio-1772 significantly reduced blood glucose levels to 242.0 ± 55.1 mg/dL (P<0.05) and increased insulin levels to 58.7 ± 14.8 pmol/L (P<0.05), indicating the hypoglycemic activity of this compound. LASSBio-1772 also reduced the elevated triglyceride levels induced by STZ treatment from 74.1 ± 8.6 to 34.0 ± 6.3 mg/dL (P<0.01). LASSBio-1772 could reduce serum glucose levels via increased insulin levels and potentially improve insulin sensitivity. Neuropathy was detected after four weeks of STZ-induced diabetes, with reduced thermal heat withdrawal latency from 11.7 ± 0.1 to 7.1 ± 0.2 s (P<0.01) and paw withdrawal threshold from 37.5 ± 2.1 to 29.9 ± 1.1 g (P<0.05) indicating the establishment of hyperalgesia and allodynia. LASSBio-1772 treatment restored both measures to non-diabetic values (12.2 ± 0.4 s and 34.5 ± 1.5 g). In conclusion, treatment with LASSBio-1772, a partial PPARgamma agonist, decreased hyperglycemia and neuropathic pain induced by diabetes. PPARgamma stimulation by LASSBio-1772 could prevent inflammation and inhibit both peripheral and central sensitization.

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Introduction: Pulmonary arterial hypertension (PAH) is a disease characterized by pulmonary vascular remodeling with subsequent right ventricular (RV) failure. The p38-alpha mitogen-activated protein kinase (p38-α MAPK) plays a pathogenic role in PAH. This work investigated the effects of a selective p38-alpha MAPK inhibitor, LASSBio-1824, on SuHx-induced PAH. Methods: Male Wistar rats (180-220 g) were exposed to 3 weeks of hypoxia and i.p. injection of VEGFR antagonist (SU5416; 20 mg/kg/week). Experimental groups were: Control + vehicle (DMSO), SuHx + vehicle (PAH group) and SuHx + LASSBio-1824 (20 mg/kg/day i.p. for 2 weeks).Results: Pulmonary acceleration time (ms) was reduced from 44.7 ± 1.1 (control) to 20.6 ± 1.7 in SuHx + vehicle group (P < 0.05) and restored to 38.9 ± 2.9 in SuHx + LASSBio-1824 group (P < 0.05). RV systolic pressures (mmHg) were increased from 30.1 ± 3.2 (control) to 109.5 ± 7.5 in SuHx group and reduced to 47.5 ± 5.3 after treatment with LASSBio-1824 (P < 0.05). The medial wall thickness of distal pulmonary arterioles (< 50 µm) was measured by immunohistochemistry for alpha-SMA expression which was increased from 40.7 ± 3.5 % (control) to 64.1 ± 3.1 % in PAH animals (P < 0.05) and was reduced in the treated group (52.2 ± 2.9). Acetylcholine-induced maximal relaxation (%) in pulmonary arteries was reduced from 77.9 ± 5.2 to 17.2 ± 3.5 in PAH group. LASSBio-1824 increased that response to 67.8 ± 5.6 % (P < 0.05), indicating the amelioration of endothelial function. RV hypertrophy was detected because its wall thickness (mm) increased from 0.56 ± 0.02 (control) to 1.3 ± 0.03 in SuHx + vehicle group (P < 0.05) and the ratio between RV and left ventricle + septum increased from 1.50 ± 0.03 to 2.0 ± 0.2. Treatment with LASSBio -1824 significantly reduced the RV hypertrophy (ratio of 1.7 ± 0.07). Conclusion:The inhibition of p38-alpha MAPK isoform by LASSBio-1824 represents an important approach for the treatment of PAH in the future, which improves the underlying remodeling and inflammation processes.

Objectives: Investigate the effects of LASSBio-1773, a ligand of PPAR-gamma receptor with hypoglycemic activity, in a model of diabetic cardiomyopathy (DC) induced by streptozotocin (STZ). Methods: Male Wistar rats received a single i.v. injection of STZ (60 mg/kg) for diabetes induction. Experimental groups were: control, STZ + vehicle, and STZ + LASSBio-1773 (50 mg/kg/day i.p.). Animals were treated with vehicle or LASSBio-1773 for 7 days after disease onset. Cardiovascular function and plasma biochemistry evaluations were performed by the end of protocol. Findings: Serum glucose, total cholesterol and triglycerides levels were significantly higher in STZ group, and treatment with LASSBio-1773 normalized both hyperglycemia and hypertriglyceridemia (Table 1). Following 8 weeks of STZ injection, echocardiography showed that left ventricular (LV) filling pressures (E/e′) increased in STZ + vehicle group. Treatment with LASSBio-1773 improved diastolic parameters in STZ-injected rats but no changes were observed on LV ejection fraction (Table 1). STZ + vehicle group have developed hypertension which was reduced after treatment with LASSBio-1773 (Table 1). Vascular dysfunction was found by the reduced acetylcholine maximum relaxation (Ach-MR) in isolated aortic rings from STZ + vehicle group which was improved with LASSBio-1773 administration. Conclusions: LASSBio-1773 improved cardiovascular function and lipid profile of diabetic rats, indicating that this novel PPAR-gamma agonist is a promising candidate for the treatment of diabetes-related cardiac complications.