Recent and emerging anti‐diabetes targets

Mohler, Michael L.; He, Yu‐Ying; Wu, Zhongzhi; Hwang, Dong-Jin; Miller, Duane D.

doi:10.1002/med.20142

Cited by 83 publications

(56 citation statements)

References 324 publications

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“…Thus, the development of alternative agents acting by novel mechanisms has become necessary to control glucose levels in patients with progressing hyperglycemia (Rotella, 2004;Skyler, 2004;Mohler et al, 2009). Some emerging small molecules primarily lower blood glucose levels by modulating targets that affect glucose metabolism (glucokinase, glycogen phosphorylase) or by regulating glucose homeostasis (AMP-activated protein kinase).…”

mentioning

confidence: 99%

In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans

Obermeier

Yao²,

Khanna³

et al. 2009

Drug Metab Dispos

156

141

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ABSTRACT:(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of [ 14 C]dapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.

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mentioning

confidence: 99%

In Vitro Characterization and Pharmacokinetics of Dapagliflozin (BMS-512148), a Potent Sodium-Glucose Cotransporter Type II Inhibitor, in Animals and Humans

Obermeier

Yao²,

Khanna³

et al. 2009

Drug Metab Dispos

156

141

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“…In addition, these drugs differ from other OADs, such as sulfonylurea and insulin, which cause weight gain. 22 Decreased blood pressure (BP), both systolic (SBP) and diastolic (DBP), was observed with SGLTi-2, without compensatory increase in heart rate. This is because, by causing glycosuria, osmotic diuresis occurs, reducing circulating volume and, consequently, BP levels.…”

Section: The Kidney As a Treatment Targetmentioning

confidence: 99%

Use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus

Santos¹,

Lima

Sousa‐Rodrigues³

et al. 2017

Rev. Assoc. Med. Bras.

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Summary Introduction: Diabetes mellitus is one of the most common chronic diseases in the world, with high morbidity and mortality rates, resulting in a greatly negative socioeconomic impact. Although there are several classes of oral antidiabetic agents, most of the patients are outside the therapeutic goal range. Objective: To review the use of SGLT-2 inhibitors in the treatment of type 2 diabetes mellitus, focusing on their favorable and unfavorable effects, as well as on cardiovascular profile. Method: A literature search on Pubmed database was performed using the following keywords: "SGLT-2 inhibitors," "dapagliflozin," "empagliflozin," "canagliflozin." Results: SGLT-2 inhibitors are a class of oral antidiabetic drugs directed to the kidney. Their mechanism of action is to reduce blood glucose by inducing glycosuria. Extra-glycemic benefits have been described, such as weight loss, decline in blood pressure and levels of triglycerides and uric acid, and they can slow the progression of kidney disease. Genitourinary infections are the main side effects. There is a low risk of hypotension and hypoglycemia. Diabetic ketoacidosis is a serious adverse effect, although rare. Empagliflozin has already had its cardiovascular benefit demonstrated and studies with other drugs are currently being performed. Conclusion: SGLT-2 inhibitors are a new treatment option for type 2 diabetes mellitus, acting independently of insulin. They have potential benefits other than the reduction of blood glucose, but also carry a risk for adverse effects.

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“…The first series of GPR119 agonists reported by Bristol-Myers Squibb featured a [6,5], [6,6], or [6,7] bicyclic central core [41,42]. Representative examples containing pyrimidine-fused pyrrazole, triazole, and morpholine ring systems are shown in Figure 8 …”

Section: Bristol-myers Squibbmentioning

confidence: 99%

“…Small molecule DPP-4 inhibitors enhance glucose-dependent insulin release by inhibiting the degradation of endogenous GLP-1 [4]. Several nonpeptide, except DPP-4 inhibitors, binding G protein-coupled receptors (GPCRs) have been deorphanized recently and are currently being evaluated as candidate GLP-1 secretagogues for T2DM [5,6]. Among these, the G protein-coupled receptor 119 (GPR119) has received considerable attention from the pharmaceutical industry in recent years.…”

Section: Introductionmentioning

confidence: 99%