Effects of SGLT2 inhibitors on the onset of esophageal varices and extrahepatic cancer in type 2 diabetic patients with suspected MASLD: a nationwide database study in Japan.

Background & Aim: SGLT2 inhibitors (SGLT2i) improve hepatic steatosis in patients with type 2 diabetes mellitus (T2DM) and MASLD. We aimed to investigate the impact of SGLT2i on the incidence of liver-related events and extrahepatic cancer compared to DPP4 inhibitors (DPP4i) in patients with T2DM and suspected MASLD using a medical claims database in Japan.

Methods: We conducted a retrospective study using a Japanese medical claims database.

TP0463518, a Novel Prolyl Hydroxylase Inhibitor, Specifically Induces Erythropoietin Production in the Liver.

Prolyl hydroxylase (PHD) 1/2/3 pan inhibitors are known to potentially induce erythropoietin (EPO) production in both the kidney and liver. The 2-[[1-[[6-(4-chlorophenoxy)pyridin-3-yl]methyl]-4-hydroxy-6-oxo-2,3-dihydropyridine-5-carbonyl]amino]acetic acid (TP0463518) is a novel PHD 1/2/3 pan inhibitor; however, the main source of EPO production after TP0463518 administration remained to be investigated. We examined the effect of TP0463518 in inducing EPO production in the kidney and liver by measuring the hypoxia-inducible factor 2 (HIF-2), EPO mRNA, and serum EPO levels in normal and bilaterally nephrectomized rats.

SGL5213, a novel and potent intestinal SGLT1 inhibitor, suppresses intestinal glucose absorption and enhances plasma GLP-1 and GLP-2 secretion in rats.

Sodium-glucose cotransporter 1 (SGLT1) is the primary transporter for glucose absorption from digested nutrients in the gastrointestinal tract. Intestinal SGLT1 inhibition reduces post-prandial hyperglycemia and enhances the increase of plasma glucagon-like peptide-1 (GLP-1) levels. SGL5213 is a novel and potent intestinal SGLT1 inhibitor.

Discovery of potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor SGL5213 for type 2 diabetes treatment.

A new series of C-phenyl d-glucitol derivatives was designed and synthesized, and their SGLT1 inhibitory potency and absorbability were evaluated. We also investigated whether kidney drug retention could be avoided by creating molecules with different excretion pathways. To achieve a class of molecules with low absorption and that were excreted in bile, optimized synthesis was performed to bring the ClogP value and the topological polar surface area to within the appropriate ranges.

Discovery of a potent, low-absorbable sodium-dependent glucose cotransporter 1 (SGLT1) inhibitor (TP0438836) for the treatment of type 2 diabetes.

The design and synthesis of a novel class of low-absorbable SGLT1 inhibitors are described. To achieve low absorption in the new series, we performed an optimization study based on a strategy to increase TPSA. Fortunately, the optimization of an aglycon moiety and a side chain of the distal aglycon moiety led to the identification of compound 30b as a potent and low-absorbable SGLT1 inhibitor.

Identification of 2-[2-(4-tert-Butylphenyl)ethyl]-N-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor.

We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC50 against human MGAT2 enzyme than 2.

Establishment of consomic strains derived from A/J and SM/J mice for genetic analysis of complex traits.

Consomic strains, in which one chromosome is derived from a donor strain and the other chromosomes are derived from the recipient strain, provide a powerful tool for the dissection of complex genetic traits. In this study we established ten consomic strains (A-2(SM), A-6(SM), A-11(SM), A-12(SM), A-13(SM), A-15(SM), A-17(SM), A-18(SM), A-19(SM), A-Y(SM)) using the SM/J strain as the donor and the A/J strain as the recipient; these are the parental strains of a set of SMXA recombinant inbred (RI) strains that we had developed previously. We analyzed body weights and blood lipid levels in the consomic and parental strains.

Discovery of novel (4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors: F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group.

Novel (4-piperidinyl)-piperazine derivatives were synthesized and evaluated as ACC1/2 non-selective inhibitors. Optimization of the substituents on the nitrogen of the piperidine ring led to the identification of the fluorine substituted tert-butoxycarbonyl group. Advanced analog, 1,1,1-trifluoro-2-methylpropan-2-yl 4-{4-[(2-amino-6-methyl-1-benzothiophen-3-yl)carbonyl]piperazin-1-yl}piperidine-1-carboxylate (12c) showed potent inhibitory activities in enzyme-assay and cell-based assays.

Design and synthesis of disubstituted (4-piperidinyl)-piperazine derivatives as potent acetyl-CoA carboxylase inhibitors.

Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the structure-based design and synthesis of a novel series of disubstituted (4-piperidinyl)-piperazine derivatives as ACC inhibitors.

(1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol (TS-071) is a potent, selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for type 2 diabetes treatment.

Derivatives of a novel scaffold, C-phenyl 1-thio-D-glucitol, were prepared and evaluated for sodium-dependent glucose cotransporter (SGLT) 2 and SGLT1 inhibition activities. Optimization of substituents on the aromatic rings afforded five compounds with potent and selective SGLT2 inhibition activities. The compounds were evaluated for in vitro human metabolic stability, human serum protein binding (SPB), and Caco-2 permeability.

(4-Piperidinyl)-piperazine: a new platform for acetyl-CoA carboxylase inhibitors.

Acetyl-CoA carboxylases (ACCs), the rate limiting enzymes in de novo lipid synthesis, play important roles in modulating energy metabolism. The inhibition of ACC has demonstrated promising therapeutic potential for treating obesity and type 2 diabetes mellitus in transgenic mice and preclinical animal models. We describe herein the synthesis and structure-activity relationships of a series of disubstituted (4-piperidinyl)-piperazine derivatives as a new platform for ACC1/2 non-selective inhibitors.

Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet.

Fatty liver is strongly associated with the metabolic syndrome characterized by obesity, insulin resistance, and type 2 diabetes, but the genetic basis and functional mechanisms linking fatty liver with the metabolic syndrome are largely unknown. The SMXA-5 mouse is one of the SMXA recombinant inbred substrains established from SM/J and A/J strains and is a model for polygenic type 2 diabetes, characterized by moderately impaired glucose tolerance, hyperinsulinemia, and mild obesity. SMXA-5 mice also developed fatty liver, and a high-fat diet markedly worsened this trait, although SM/J and A/J mice are resistant to fatty liver development under a high-fat diet.

SMXA-5 mouse as a diabetic model susceptible to feeding a high-fat diet.

The SMXA-5 strain, a new mouse model for type 2 diabetes, is a recombinant inbred strain derived from non-diabetic SM/J and A/J strains. As dietary fat is a key component in the development of diabetes, we compared the glucose tolerance and diabetes-related traits among the SMXA-5, SM/J, and A/J strains while feeding a high-fat diet for 10 weeks. SMXA-5 fed on a high-fat diet showed an increased serum insulin concentration.