Inhibitor Report for: Saxagliptin

INTRODUCTION: Dipeptide peptidase-4 (DPP-4) inhibitors such as saxagliptin are established and efficacious oral therapies in the management of type 2 diabetes. These agents have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes. AREAS COVERED: This review examines the pharmacokinetics, efficacy and tolerability of saxagliptin for the management of type 2 diabetes. EXPERT OPINION: Saxagliptin is routinely used in the management of type 2 diabetes as monotherapy, and in combination with other oral agents and insulin. Robust clinical trials have shown consistent improvements in glycated hemoglobin, fasting and postprandial glucose levels, with few adverse effects. The agent is well tolerated with low rates of hypoglycemia in the absence of insulin or sulphonylurea therapy.

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic beta-cells and subsequent lowering of blood glucose levels, HbA[1(c)], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.

The inhibition of DPP-IV by saxagliptin has been proposed to occur through formation of a covalent but reversible complex. To evaluate further the mechanism of inhibition, we determined the X-ray crystal structure of the DPP-IV:saxagliptin complex. This structure reveals covalent attachment between S630 and the inhibitor nitrile carbon (C-O distance <1.3 A). To investigate whether this serine addition is assisted by the catalytic His-Asp dyad, we generated two mutants of DPP-IV, S630A and H740Q, and assayed them for ability to bind inhibitor. DPP-IV H740Q bound saxagliptin with an approximately 1000-fold reduction in affinity relative to DPP-IV WT, while DPP-IV S630A showed no evidence for binding inhibitor. An analog of saxagliptin lacking the nitrile group showed unchanged binding properties to the both mutant proteins, highlighting the essential role S630 and H740 play in covalent bond formation between S630 and saxagliptin. Further supporting mechanism-based inhibition by saxagliptin, NMR spectra of enzyme-saxagliptin complexes revealed the presence of three downfield resonances with low fractionation factors characteristic of short and strong hydrogen bonds (SSHB). Comparison of the NMR spectra of various wild-type and mutant DPP-IV:ligand complexes enabled assignment of a resonance at approximately 14 ppm to H740. Two additional DPP-IV mutants, Y547F and Y547Q, generated to probe potential stabilization of the enzyme-inhibitor complex by this residue, did not show any differences in inhibitor binding either by ITC or NMR. Together with the previously published enzymatic data, the structural and binding data presented here strongly support a histidine-assisted covalent bond formation between S630 hydroxyl oxygen and the nitrile group of saxagliptin.

INTRODUCTION: Dipeptide peptidase-4 (DPP-4) inhibitors such as saxagliptin are established and efficacious oral therapies in the management of type 2 diabetes. These agents have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes. AREAS COVERED: This review examines the pharmacokinetics, efficacy and tolerability of saxagliptin for the management of type 2 diabetes. EXPERT OPINION: Saxagliptin is routinely used in the management of type 2 diabetes as monotherapy, and in combination with other oral agents and insulin. Robust clinical trials have shown consistent improvements in glycated hemoglobin, fasting and postprandial glucose levels, with few adverse effects. The agent is well tolerated with low rates of hypoglycemia in the absence of insulin or sulphonylurea therapy.

Although previous studies have shown an important role of renal dipeptidyl peptidase-4 (DPP-4) inhibition in ameliorating kidney injury in hypertensive rats, the renal distribution of DPP-4 and mechanisms of renoprotective action of DPP-4 inhibition remain unclear. In this study, we examined the effects of the DPP-4 inhibitor saxagliptin on DPP-4 activity in renal cells (using in situ DPP-4 staining) and on renal gene expression related to inflammation and fibrosis in the renal injury in hypertensive Dahl salt-sensitive (Dahl-S) rats. Male rats fed a high-salt (8% NaCl) diet received vehicle (water) or saxagliptin (12.7mg/kg/day) for 4 weeks. Blood pressure (BP), serum glucose and 24-h urinary albumin and sodium excretions were measured, and renal histopathology was performed. High salt-diet increased BP and urinary albumin excretion, consequently resulting in glomerular sclerosis and tubulointerstitial fibrosis. Although saxagliptin did not affect BP and blood glucose levels, it significantly ameliorated urinary albumin excretion. In situ staining showed DPP-4 activity in glomerular and tubular cells. Saxagliptin significantly suppressed DPP-4 activity in renal tissue extracts and in glomerular and tubular cells. Saxagliptin also significantly attenuated the increase in inflammation and fibrosis-related gene expressions in the kidney. Our results demonstrate that saxagliptin inhibited the development of renal injury independent of its glucose-lowering effect. Glomerular and tubular DPP-4 inhibition by saxagliptin was associated with improvements in albuminuria and the suppression of inflammation and fibrosis-related genes. Thus, local glomerular and tubular DPP-4 inhibition by saxagliptin may play an important role in its renoprotective effects in Dahl-S rats.

INTRODUCTION: The worldwide prevalence of type 2 diabetes mellitus (T2DM) is high, and the chronically poor metabolic control that can result from T2DM is associated with a high risk for microvascular and macrovascular complications. Because of the progressive pathophysiology of T2DM, oral antidiabetic agents often fail to provide sustained glycemic control, indicating the need for new therapies. Saxagliptin (Onglyza; Bristol-Myers Squibb Company, Princeton, NJ, USA; AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA) is an oral dipeptidyl peptidase-4 inhibitor, recently approved for the treatment of T2DM. EVIDENCE REVIEW: Saxagliptin significantly improves glycemic control vs placebo, as demonstrated by decreasing glycated hemoglobin, fasting plasma glucose, and postprandial plasma glucose levels when used as monotherapy; in initial combination with metformin; and as add-on therapy with metformin, sulfonylurea (SU), or thiazolidinedione (TZD). Saxagliptin also significantly improves beta-cell function, is weight neutral, has a low risk for hypoglycemia, and has been shown to have cardiovascular safety. PLACE IN THERAPY: The clinical profile for saxagliptin indicates that it is useful as an adjunct to diet and exercise as first-line monotherapy and in combination with metformin; or as add-on treatment for patients who cannot achieve glycemic control with a combination of diet and lifestyle changes and metformin, SU, or TZD.

Type 2 diabetes mellitus is a common chronic disease that causes significant morbidity and mortality worldwide. The primary goal of treatment is to target glycemic control by maintaining the glycosylated hemoglobin (HbA1c) level near 6% to 7% without predisposing patients to hypoglycemia. Currently available antidiabetic agents work by different mechanisms to lower blood glucose levels. Unfortunately, each of them has its tolerability and safety concerns that limit use and dose titration. Dipeptidyl peptidase-4 enzyme inhibitors are novel drugs that prolong the action of incretins, and lead to increased insulin secretion and reduced hepatic glucose production. Saxagliptin is another dipeptidyl peptidase-4 (after sitagliptin) that is approved for the management of type 2 diabetes. It can be used alone or in combination with metformin, sulfonylurea, or thiazolidinedione (pioglitazone or rosiglitazone) when treatment with one drug alone provides inadequate glucose control. The usual adult dose is 2.5 to 5 mg once daily regardless of meals. A daily dose of 2.5 mg is recommended for patients with moderate to severe renal impairment or those who are taking potent CYP 3A4 inhibitors. In randomized clinical trials, saxagliptin alone lowered HbA1c levels by about 0.5%; with better efficacy seen when combined with other agents. It is well tolerated with the most common side effects being upper respiratory tract infection, headache, and urinary tract infection. In summary, saxagliptin is an option as an adjunct to lifestyle modifications and other antidiabetic agents to target glycemic control. It is also an alternative therapy for patients who have contraindications or intolerability to other antidiabetic agents.

PURPOSE: The pharmacology, pharmacokinetics, efficacy, safety, and dosage and administration of saxagliptin are reviewed. SUMMARY: Saxagliptin is a selective, reversible inhibitor of dipeptidyl peptidase-4 (DPP-4) approved for the treatment of type 2 diabetes mellitus in adults. By inhibiting DPP-4, saxagliptin reduces the degradation of endogenous incretin hormones, resulting in increased glucose-dependent insulin release and decreased glucagon secretion from the pancreas. Saxagliptin is rapidly absorbed after oral administration, and its pharmacokinetic profile allows for once-daily oral administration. Clinical trials of saxagliptin as monotherapy and as combination therapy with other oral antidiabetic medications including metformin, glyburide, pioglitazone, and rosiglitazone have demonstrated clinical benefits in various glycemic endpoints, including glycosylated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), and postprandial glucose (PPG) levels over 24 to 102 weeks of therapy. Due to its glucose-dependent mechanism of action, saxagliptin as monotherapy or in combination with metformin results in a low risk for hypoglycemia in patients with type 2 diabetes. Saxagliptin was generally well tolerated in clinical trials, with headache, upper-respiratory-tract infection, and urinary tract infection being the most common adverse events. Saxagliptin has demonstrated a low risk for drug-drug interactions. For patients with moderate or severe renal impairment or end-stage renal disease or patients taking a strong inhibitor of cytochrome P-450 isoenzyme 3A4 or 3A5, the recommended dosage is 2.5 mg once daily. CONCLUSION: Saxagliptin, a DPP-4 inhibitor approved for the treatment of type 2 diabetes, demonstrated safety and efficacy in lowering HbA(1c), FPG, and PPG levels as both monotherapy and in combination with other oral antidiabetic medications.

Inhibition of dipeptidyl peptidase-4 (DPP-4) is a novel oral treatment for type 2 diabetes. DPP-4 inhibition increases insulin secretion and reduces glucagon secretion by preventing the inactivation of glucagon-like peptide-1 (GLP-1), thereby lowering glucose levels. Several DPP-4 inhibitors are in clinical development; more studies exist for sitagliptin and vildagliptin. They improve metabolic control in type 2 diabetes in monotherapy and also in combination with metformin, sulphonylurea and thiazolidinediones. HbA(1c) is reduced by approximately 0.6-1.1% in studies up to 52 weeks. Similar, although more limited, results were obtained for saxagliptin. DPP-4 inhibitors are safe and tolerable with no increased risk of adverse events compared to placebo and have a low risk of hypoglycaemia. DPP-4 inhibitors are body weight-neutral. The DPP-4 inhibitors are recommended for use in the early stage of type 2 diabetes, in combination with metformin in subjects with inadequate glycaemic control. DPP-4 inhibition may also be used in combination with sulphonylurea and thiazolidinediones and potentially also in combination with insulin. The durability and long-term safety of DPP-4 inhibitors remain to be established.

Saxagliptin is a potent and selective reversible inhibitor of dipeptidyl peptidase-4, which is being developed for the treatment of type 2 diabetes. It is absorbed rapidly after oral administration and has a pharmacokinetic profile compatible with once daily dosing. Saxagliptin is metabolized in vivo to form an active metabolite, and both parent drug and metabolite are excreted primarily via the kidneys. Saxagliptin reduces the degradation of the incretin hormone glucagon-like peptide-1, thereby enhancing its actions, and is associated with improved beta-cell function and suppression of glucagon secretion. Clinical trials of up to 24 weeks duration have shown that saxagliptin improves glycemic control in monotherapy and provides additional efficacy when used in combination with other oral antidiabetic agents (metformin, sulfonylurea, thiazolidinedione). Both fasting and postprandial glucose concentrations are reduce leading to clinically meaningful reductions in glycated hemoglobin, and due to the glucose-dependency of its mechanism of action, there is a low risk of hypoglycemia. Saxagliptin is reported to be well tolerated with a side-effect profile similar to placebo. It has a neutral effect on body weight and dose adjustment because of age, gender, or hepatic impairment is not necessary. Saxagliptin is being co-developed by Bristol-Myers-Squibb (New York, NY, USA) and AstraZeneca (Cheshire, UK), and is currently undergoing regulatory review.

Saxagliptin is a potent, selective, reversible dipeptidyl peptidase 4 (DPP4) inhibitor specifically designed for extended inhibition of the DPP4 enzyme and is currently under development for the treatment of type-2 diabetes. The pharmacokinetics of saxagliptin were evaluated in rats, dogs, and monkeys and used to predict its human pharmacokinetics. Saxagliptin was rapidly absorbed and had good bioavailability (50-75%) in the species tested. The plasma clearance of saxagliptin was higher in rats (115 ml/min/kg) than in dogs (9.3 ml/min/kg) and monkeys (14.5 ml/min/kg) and was predicted to be low to moderate in humans. The plasma elimination half-life was between 2.1 and 4.4 h in rats, dogs, and monkeys, and both metabolism and renal excretion contributed to the overall elimination. The primary metabolic clearance pathway involved the formation of a significant circulating, pharmacologically active hydroxylated metabolite, M2. The volume of distribution values observed in rats, dogs, and monkeys (1.3-5.2 l/kg) and predicted for humans (2.7 l/kg) were greater than those for total body water, indicating extravascular distribution. The in vitro serum protein binding was low (< or =30%) in rats, dogs, monkeys, and humans. After intra-arterial administration of saxagliptin to Sprague-Dawley and Zucker diabetic fatty rats, higher levels of saxagliptin and M2 were observed in the intestine (a proposed major site of drug action) relative to that in plasma. Saxagliptin has prolonged pharmacodynamic properties relative to its plasma pharmacokinetic profile, presumably due to additional contributions from M2, distribution of saxagliptin and M2 to the intestinal tissue, and prolonged dissociation of both saxagliptin and M2 from DPP4.

Dipeptidyl peptidase IV (DPP IV) is a key regulator of insulin-stimulating hormones, glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), thus it is a promising target for the treatment of Type 2 Diabetes mellitus (T2DM). Inhibition of plasma DPP IV enzyme leads to enhanced endogenous GLP-1 and GIP activity, which ultimately results in the potentiation of insulin secretion by pancreatic beta-cells and subsequent lowering of blood glucose levels, HbA[1(c)], glucagon secretion and liver glucose production. Various classes of structurally different DPP IV inhibitors are currently being explored and few of them such as Sitagliptin and Vildagliptin were successfully launched. These drugs have been approved as a once-daily oral monotherapy or as a combination therapy with current anti-diabetic agents like pioglitazone, glibenclamide, metformin etc. for the treatment of T2DM. Several other novel DPP IV inhibitors are in pipeline. The present review summarizes the latest preclinical and clinical trial data of different DPP IV inhibitors with a special emphasis on their DPP8/9 fold selectivity and therapeutic advantages over GLP-1 based approach.

Saxagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor, is currently under development by Bristol-Myers Squibb Co, AstraZeneca plc and Otsuka Pharmaceutical Co Ltd for the treatment of type 2 diabetes. The compound has high selectivity for DPP-IV compared with other dipeptidyl peptidases and a duration profile designed for once-daily dosing. DPP-IV inhibitors act by increasing levels of glucagon-like peptide-1, which stimulates insulin secretion. In animal studies, saxagliptin improved glucose clearance and raised insulin levels in rodents. Clinical trials have demonstrated a dose-dependent inhibition of DPP-IV by saxagliptin without serious side effects. Results have demonstrated that treatment with saxagliptin lowers blood glucose levels, with good tolerability and safety. The specific advantages of saxagliptin over other DPP-IV inhibitors may lie in its long-lived, effective and highly specific inhibition of DPP-IV, making once-daily treatment feasible, effective and safe.

The inhibition of DPP-IV by saxagliptin has been proposed to occur through formation of a covalent but reversible complex. To evaluate further the mechanism of inhibition, we determined the X-ray crystal structure of the DPP-IV:saxagliptin complex. This structure reveals covalent attachment between S630 and the inhibitor nitrile carbon (C-O distance <1.3 A). To investigate whether this serine addition is assisted by the catalytic His-Asp dyad, we generated two mutants of DPP-IV, S630A and H740Q, and assayed them for ability to bind inhibitor. DPP-IV H740Q bound saxagliptin with an approximately 1000-fold reduction in affinity relative to DPP-IV WT, while DPP-IV S630A showed no evidence for binding inhibitor. An analog of saxagliptin lacking the nitrile group showed unchanged binding properties to the both mutant proteins, highlighting the essential role S630 and H740 play in covalent bond formation between S630 and saxagliptin. Further supporting mechanism-based inhibition by saxagliptin, NMR spectra of enzyme-saxagliptin complexes revealed the presence of three downfield resonances with low fractionation factors characteristic of short and strong hydrogen bonds (SSHB). Comparison of the NMR spectra of various wild-type and mutant DPP-IV:ligand complexes enabled assignment of a resonance at approximately 14 ppm to H740. Two additional DPP-IV mutants, Y547F and Y547Q, generated to probe potential stabilization of the enzyme-inhibitor complex by this residue, did not show any differences in inhibitor binding either by ITC or NMR. Together with the previously published enzymatic data, the structural and binding data presented here strongly support a histidine-assisted covalent bond formation between S630 hydroxyl oxygen and the nitrile group of saxagliptin.

An efficient biocatalytic method has been developed for the conversion of (5S)-4,5-dihydro-1H-pyrrole-1,5-dicarboxylic acid, 1-(1,1-dimethylethyl)-5-ethyl ester (1) into the corresponding amide (5S)-5-aminocarbonyl-4,5-dihydro-1H-pyrrole-1-carboxylic acid, 1-(1,1-dimethylethyl)ester (2), which is a critical intermediate in the synthesis of the dipeptidyl peptidase IV (DPP4) inhibitor Saxagliptin (3). Candida antartica lipase B mediates ammonolysis of the ester with ammonium carbamate as ammonia donor to yield up to 71% of the amide. The inclusion of Ascarite and calcium chloride as adsorbents for carbon dioxide and ethanol byproducts, respectively, increases the yield to 98%, thereby offering an efficient and practical alternative to chemical routes which yield 57-64%.

Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.