AMG 131 / Coherus Biosci - LARVOL DELTA

Anti-viral and anti-inflammatory effects of novel PPARγ agonist, INT131, in an EcoHIV mouse model: relevance to the treatment of HIV-associated neurocognitive disorders (AIDS 2024) - "Our findings suggest PPAR? as a potential target for treating/preventing HIV-associated brain inflammation, BBB dysfunction, and potentially HAND. Future studies will explore INT131's efficacy in reversing neurocognitive deficits (motor, learning and memory) in the EcoHIV mouse model through behavioural assessments."

Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Infectious Disease • Inflammation • Metabolic Disorders • CASP3 • CLDN5 • GFAP • IL1B • IL6 • OCLN • PPARG • TJP1 • TNFA

Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment. (PubMed, J Biomol Struct Dyn) - "Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data...The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (-13.9 kcal/mol and -86.2 kcal/mol), A1 (-11.1 kcal/mol and -79.5 kcal/mol), A13 (-11.3 kcal/mol and -91.4 kcal/mol), and the co-crystal itself (-9.8 kcal/mol and -76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and β-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein.Communicated by Ramaswamy H. Sarma."

Journal • Bipolar Disorder • CNS Disorders • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • PPARG

Effects of KY-903, a Novel Tetrazole-Based Peroxisome Proliferator-Activated Receptor γ Modulator, in Male Diabetic Mice and Female Ovariectomized Rats. (PubMed, Biol Pharm Bull) - "The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. In mesenchymal stem cell-like ST2 cells, KY-903 slightly reduced osteoblast differentiation without adipocyte differentiation, while pioglitazone markedly reduced it with adipocyte differentiation. In conclusion, KY-903 is a novel PPARγ modulator that exerts anti-diabetic effects without body weight gain or cardiac hypertrophy in diabetic mice and anti-obesity effects with minor bone loss in OVX/HFD, possibly due to increases in adiponectin levels without adipogenesis."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Osteoporosis

Current and emerging pharmacological options for the treatment of nonalcoholic steatohepatitis. (PubMed, Metabolism) - "Some of these medications are currently in phase 3 clinical trials, including obeticholic acid (a farnesoid X receptor agonist), elafibranor (a peroxisome proliferator activated receptor [PPAR]-α/δ dual agonist), cenicriviroc (a CC chemokine receptor antagonist), MSDC-0602 K (a PPAR sparing modulator), selonsertib (an apoptosis signal-regulating kinase-1 inhibitor) and resmetirom (a thyroid hormone receptor agonist). A significant research effort is also targeting PPARs and selective PPAR modulators, including INT131 and pemafibrate, with the expectation that novel drugs may have beneficial effects similar to those of pioglitazone, but without the associated adverse effects. Whether these and other medications could offer tangible therapeutic benefits, alone or in combination, apparently on a background of lifestyle modification, i.e. exercise and a healthy dietary pattern e.g. Mediterranean diet remains to be proven. In conclusion, major advances are expected for the..."

Journal • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Selective peroxisome proliferator-activated receptor-gamma modulator, INT131 exhibits anti-inflammatory effects in an EcoHIV mouse model. (PubMed, FASEB J) - "Pharmacokinetic analyses revealed that INT131 penetrates into the brain with a brain to blood partition ratio Kp value of 8.5%. Overall, this is the first report to demonstrate that INT131 could be a potential candidate for the treatment of HIV-1-associated brain inflammation."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Human Immunodeficiency Virus • Immunology • Infectious Disease • Inflammation

[VIRTUAL] The selective PPAR gamma modulator CHS-131 improves liver histopathology and metabolism in a biopsy-confirmed mouse model of non-alcoholic steatohepatitis and obesity (EASD 2020) - "CHS-131 can be an effective treatment in NASH by improving hepatic lipid composition, reducing lobular inflammation and hepatocyte ballooning and decreasing markers of hepatic fibrosis. The beneficial effects of CHS-131 on NASH are most probably achieved indirectly by changes in visceral and subcutaneous adipose tissue function, elevated adiponectin levels and systemic improvement of insulin sensitivity. Treatment with CHS-131 was not associated with common side effects observed in full PPARᵧ activators, such as water retention and weight gain."

Preclinical • Metabolic Disorders • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • CCL2 • COL1A1 • FASN • PPARG

The Selective Peroxisome Proliferator-Activated Receptor Gamma Modulator CHS-131 Improves Liver Histopathology and Metabolism in a Mouse Model of Obesity and Nonalcoholic Steatohepatitis. (PubMed, Hepatol Commun) - "DIO-NASH mice treated with CHS-131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. CHS-131 improves liver histology in a DIO and biopsy-confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue."

Journal • Preclinical • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Metabolic Disorders • Non-alcoholic Steatohepatitis • Obesity • PPARG

Discovery of INT131: A selective PPARγ modulator that enhances insulin sensitivity (Bioorg Med Chem) - "...describes the discovery of a novel chemical class of diarylsulfonamide partial agonists that act as selective PPARγ modulators (SPPARγMs) and display a unique pharmacological profile compared to the thiazolidinedione (TZD) class of PPARγ full agonists."

Review • Diabetes

Int131 Besylate, a selective PPARγ modulator (SPPARM), improved glycemic control in patients with type 2 diabetes without causing the edema seen with Pioglitazone (ADA 2010) - P=NA, N=366; INT131 improved glycemic control when given to patients with T2DM not adequately controlled on standard of care therapy (SU/Met or SU) without evidence of any significant change in edema compared to baseline or placebo

Diabetes

Structure-Activity Relationship of 2,4-dichloro-N-(3,5-dichloro-4-(quinolin-3-yloxy)phenyl)benzenesulfonamide (INT131) Analogs for PPARγ-Targeted Antidiabetics. (PubMed) - "To probe the structure-activity relationship (SAR) of the scaffold 1, we synthesized 14 analogs of compound 1 which revealed compounds with higher transcriptional potency for PPARγ and identification of moieties of the scaffold 1 key to high transcriptional potency. The sulfonamide linker is critical to activity, substitutions at position 4 of the benzene ring A were associated with higher transcriptional activity, substitutions at position 2 aided in tighter packing and activity, and the ring type and size of ring A affected the degree of activity."

Journal • Biosimilar • Diabetes • Metabolic Disorders

Identification and structural insight of an effective PPARγ modulator with improved therapeutic index for anti-diabetic drug discovery. (PubMed, Chem Sci) - "We have also determined the co-crystal structure of the PPARγ ligand-binding domain (LBD) in complex with two molecules of (S)-VSP-77, which reveal a previously undisclosed allosteric binding mode. Overall, these findings not only demonstrate the therapeutic advantage of (S)-VSP-77 over current TZD drugs and representative partial agonist INT131, but also provide a rational basis for the development of future SPPARγMs as safe and highly efficacious anti-diabetic drugs."

Journal

A Novel Peroxisome Proliferator-activated Receptor-γ (PPARγ) agonist (INT131) exhibits anti-inflammatory effects in an animal model of HIV-1 associated brain inflammation (IAS-HIV 2019) - "Information about the poster discussion and poster exhibition abstracts may not be published or presented before 10:00 (Central Daylight Time (CDT)) on Monday, 22 July 2019."

Preclinical