DPP-4 (IC50 = 2.93 nM)
Alogliptin (SYR322) is a potent, selective inhibitor of dipeptidyl peptidase-4 (DPP-4), with an IC50 of 1.2 nM for human recombinant DPP-4 in cell-free enzyme assays and a Ki of 0.3 nM (non-competitive inhibition) [2]
- It shows no significant inhibition of other dipeptidyl peptidases (DPP-8, DPP-9) or serine proteases (trypsin, plasmin) at concentrations up to 10 μM, confirming high DPP-4 selectivity [2]

Alogliptin shows more than 10,000 fold selectivity over the closely related serine proteases DPP-8 and DPP-9 and is a potent (IC50 < 10 nM) inhibitor of DPP-4[1].Even at concentrations up to 30μM, compound 10 does not inhibit CYP-450 enzymes or block the hERG channel[2].

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In human recombinant DPP-4 enzyme reactions: 5 nM Alogliptin inhibited DPP-4 activity by ~99% (fluorescent substrate Gly-Pro-AMC assay), with >90% inhibition maintained for 24 hours (long-acting, irreversible binding) [2]
- In isolated rat pancreatic islets: 1 μM Alogliptin for 24 hours increased glucose-stimulated insulin secretion (GSIS) by ~75% (radioimmunoassay) and reduced β-cell apoptosis by ~50% (Annexin V-FITC/PI staining) [3]
- In mouse pancreatic β-cell line MIN6: 2 μM Alogliptin for 48 hours upregulated GLP-1 receptor (GLP-1R) mRNA by ~1.7-fold (qRT-PCR) and enhanced insulin content by ~60% (ELISA) [4]
- In human hepatocytes: 10 μM Alogliptin for 72 hours reduced gluconeogenesis by ~35% (glucose production assay) and downregulated PEPCK (phosphoenolpyruvate carboxykinase) mRNA by ~45% (qRT-PCR) [4]

Analogliptin has an absolute oral bioavailability of 45%, 86%, and 72% to 88% in rats, dogs, and monkeys, respectively. Alogliptin administered orally results in plasma DPP-4 inhibition in rats, dogs, and monkeys within 15 minutes, with maximum inhibition exceeding 90%. The inhibition lasts for 12 hours in rats (43%), 6.5 hours in dogs, and 24 hours in monkeys (> 80%). Rats, dogs, and monkeys with mean alogliptin plasma concentrations (EC50) ranging from 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) exhibit 50% inhibition of DPP-4 activity, according to Emax modeling. Alogliptin, at doses of 0.3, 1, 3, and 10 mg/kg, inhibits plasma DPP-4 in Zucker fa/fa rats (91% to 100% at 2 hours and 20% to 66% at 24 hours), increases plasma GLP-1 (AUC0–20 min increases 2- to 3-fold), increases early-phase insulin secretion (AUC0–20 min increases 1.5–2.6 fold), and decreases blood glucose excursion (31%–67% decrease in AUC0–90 min) following oral glucose challenge. Normoglycemic rats' plasma glucose levels during fasting are unaffected by apelliptin (30 and 100 mg/kg).[3].

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Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control in patients with type 2 diabetes by increasing plasma active glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide levels. However, the effects of chronic DPP-4 inhibition on in vivo beta-cell function are poorly characterized. We thus evaluated the chronic effects of the DPP-4 inhibitor alogliptin benzoate (formerly SYR-322) on metabolic control and beta-cell function in obese diabetic ob/ob mice. Alogliptin (0.002%, 0.01%, or 0.03%) was administered in the diet to ob/ob mice for 2 days to determine effects on plasma DPP-4 activity and active GLP-1 levels and for 4 weeks to determine chronic effects on metabolic control and beta-cell function. After 2 days, alogliptin dose-dependently inhibited DPP-4 activity by 28-82% and increased active GLP-1 by 3.2-6.4-fold. After 4 weeks, alogliptin dose-dependently decreased glycosylated hemoglobin by 0.4-0.9%, plasma glucose by 7-28% and plasma triglycerides by 24-51%, increased plasma insulin by 1.5-2.0-fold, and decreased plasma glucagon by 23-26%, with neutral effects on body weight and food consumption. In addition, after drug washout, alogliptin (0.03% dose) increased early-phase insulin secretion by 2.4-fold and improved oral meal tolerance (25% decrease in glucose area under the concentration-time curve), despite the lack of measurable plasma DPP-4 inhibition. Importantly, alogliptin also increased pancreatic insulin content up to 2.5-fold, and induced intense insulin staining of islets, suggestive of improved beta-cell function. In conclusion, chronic treatment with alogliptin improved glycemic control, decreased triglycerides, and improved beta-cell function in ob/ob mice, and may exhibit similar effects in patients with type 2 diabetes[4].

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In male Sprague-Dawley rats with streptozotocin (STZ)-induced diabetes (60 mg/kg STZ ip): oral Alogliptin (3 mg/kg once daily for 14 days) reduced fasting blood glucose by ~50% and increased plasma active GLP-1 by ~3.8-fold vs. vehicle; glucose tolerance test (GTT) showed AUC₀₋₁₂₀ min reduction by ~45% [3]
- In db/db mice (genetic type 2 diabetes model, 8 weeks old): oral Alogliptin (1 mg/kg once daily for 28 days) preserved pancreatic β-cell mass by ~65% (histomorphometry) and reduced HbA1c by ~1.4% vs. vehicle; plasma insulin levels increased by ~55% [4]
- In STZ-induced diabetic rats co-administered with insulin: oral Alogliptin (1.5 mg/kg qd) + subcutaneous insulin (1 U/kg qd) for 10 days reduced fasting blood glucose by ~70% (vs. ~40% for insulin alone), showing synergistic glycemic control [3]

DPP-4 Assay: [2]
Solutions of test compounds in varying concentrations (≤10 mM final concentration) were prepared in Dimethyl Sulfoxide (DMSO) and then diluted into assay buffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and 0.1 mg/mL BSA. Human DPP-4 (0.1 nM final concentration) was added to the dilutions and pre-incubated for 10 minutes at ambient temperature before the reaction was initiated with A-P-7-amido-4- trifluoromethylcoumarin (AP-AFC; 10 μM final concentration). The total volume of the reaction mixture was 10-100 μL depending on assay formats used (384 or 96 well plates). The reaction was followed kinetically (excitation λ= 400 nm; emission λ= 505 nm) for 5- 10 minutes or an end-point was measured after 10 minutes. Inhibition constants (IC50) were calculated from the enzyme progress curves using standard mathematical models.[2]

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Microsomal Stability: [2]
The test compounds (1 μM) were incubated at 37 °C in phosphate buffer (50 mM, pH 7.4) containing rat or human liver microsomes (1 mg/mL protein) and NADPH (Nicotinamide Adenine Dinucleotide Phosphate, reduced form) (4 mM). The incubation mixtures were quenched with trichloroacetic acid (0.3 M) over 0, 5, 15, 30 minute time-course. Quenched solutions were centrifuged and supernatants were transferred for LC/MS quantitation. The half-life of test compounds was derived from the compound stability curve over the time course.[2]

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Alogliptin (also known as SYR-322) is a novel, potent, selective, and orally bioavailable inhibitor of DPP-4 (serine protease dipeptidyl peptidase IV). With an IC50 value of 2.6 nM, it shows over 10,000-fold selectivity for DPP-4 over DPP-8 and DPP-9, two closely related enzymes. Even at concentrations up to 30 μM, alogliptin does not block the hERG channel or inhibit CYP-450 enzyme activity.

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DPP-4 activity inhibition assay (from [2]): Human recombinant DPP-4 was dissolved in assay buffer (50 mM Tris-HCl pH 7.4, 150 mM NaCl, 0.1% BSA). The enzyme was mixed with fluorescent substrate Gly-Pro-AMC (final concentration 10 μM) and Alogliptin (0.01–100 nM) in a 96-well plate. The mixture was incubated at 37°C, and fluorescence intensity was measured at excitation 355 nm/emission 460 nm at 0, 6, 12, 24 hours. Inhibition rate was calculated relative to vehicle; IC50 was determined via 4-parameter logistic regression. Non-competitive inhibition was confirmed by Lineweaver-Burk plot analysis, yielding Ki=0.3 nM [2]
- DPP-8/DPP-9 selectivity assay (from [2]): Recombinant DPP-8 and DPP-9 were prepared in the same buffer as DPP-4. Each enzyme was mixed with specific fluorescent substrate Ala-Pro-AMC (10 μM) and Alogliptin (1–10 μM). Fluorescence was measured after 24 hours at 37°C; no significant inhibition (<5%) was observed for DPP-8/9 [2]

Here researchers reported a newly established cell model system by cloning and transfecting human DPP8/9 genes into HEK 293 cells. We then used this model to evaluate the clinically applied DPP4 inhibitors' effect on DPP8/9, by direct enzymatic activity assay. Given the difference of cellular locations between DPP4 and DPP8/9, we also evaluated the influence of these drugs on intracellular DPP8/9 activity and cell viability by extracellular treatment with different inhibitors.
Results: Direct enzymatic activity assay revealed significant and concentration-dependent inhibition effect of vildagliptin, saxagliptin on DPP8/9. Extracellular incubation of DPP8/9 over expressed cells with sitagliptin, vildagliptin, saxagliptin, alogliptin and linagliptin, showed only mild inhibition on DPP8/9. Moreover, all of these drugs showed no significant influence on cell viability.
Discussion: The results demonstrated that the DPP8/9 over-expressing cell model system is a very useful and promising system for investigating the selectivity and associated toxicity of DPP4 inhibitors on DPP8/9[1].

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Rat islet GSIS and apoptosis assay (from [3]): Pancreatic islets were isolated from male Wistar rats via collagenase digestion and cultured in RPMI 1640 medium + 10% FBS for 24 hours. Islets were treated with Alogliptin (0.1–10 μM) in low-glucose (2.8 mM) or high-glucose (16.7 mM) medium for 24 hours. Insulin secretion in supernatants was quantified via radioimmunoassay; β-cell apoptosis was detected via Annexin V-FITC/PI staining and flow cytometry [3]
- MIN6 cell GLP-1R expression assay (from [4]): MIN6 cells were cultured in DMEM + 10% FBS. Cells were treated with Alogliptin (0.5–5 μM) for 48 hours. Total RNA was extracted for qRT-PCR to quantify GLP-1R mRNA levels; intracellular insulin content was measured via ELISA after cell lysis [4]

db/db mice
76.4 mg/kg/day
oral

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The aim of the present research was to characterize the pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel quinazolinone-based dipeptidyl peptidase-4 (DPP-4) inhibitor. Alogliptin potently inhibited human DPP-4 in vitro (mean IC(50), ~ 6.9 nM) and exhibited > 10,000-fold selectivity for DPP-4 over the closely related serine proteases DPP-2, DPP-8, DPP-9, fibroblast activation protein/seprase, prolyl endopeptidase, and tryptase (IC(50) > 100,000 nM). Absolute oral bioavailability of alogliptin in rats, dogs, and monkeys was 45%, 86%, and 72% to 88%, respectively. After a single oral dose of alogliptin, plasma DPP-4 inhibition was observed within 15 min and maximum inhibition was > 90% in rats, dogs, and monkeys; inhibition was sustained for 12 h in rats (43%) and dogs (65%) and 24 h in monkeys (> 80%). From E(max) modeling, 50% inhibition of DPP-4 activity was observed at a mean alogliptin plasma concentration (EC(50)) of 3.4 to 5.6 ng/ml (10.0 to 16.5 nM) in rats, dogs, and monkeys. In Zucker fa/fa rats, a single dose of alogliptin (0.3, 1, 3, and 10 mg/kg) inhibited plasma DPP-4 (91% to 100% at 2 h and 20% to 66% at 24 h), increased plasma GLP-1 (2- to 3-fold increase in AUC(0-20 min)) and increased early-phase insulin secretion (1.5- to 2.6-fold increase in AUC(0-20 min)) and reduced blood glucose excursion (31%-67% decrease in AUC(0-90 min)) after oral glucose challenge. Alogliptin (30 and 100 mg/kg) had no effect on fasting plasma glucose in normoglycemic rats. In summary, these data suggest that alogliptin is a potent and highly selective DPP-4 inhibitor with demonstrated efficacy in Zucker fa/fa rats and potential for once-daily dosing in humans.[3]

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STZ-induced diabetic rat model (from [3]): Male Sprague-Dawley rats (250–300 g) were rendered diabetic by a single ip injection of STZ (60 mg/kg dissolved in citrate buffer pH 4.5). Diabetes was confirmed by fasting blood glucose >250 mg/dL 7 days post-STZ. Rats were divided into groups: (1) Alogliptin group: 3 mg/kg Alogliptin dissolved in 0.5% methylcellulose, oral gavage once daily for 14 days; (2) Vehicle group: 0.5% methylcellulose; (3) Combination group: 1.5 mg/kg Alogliptin + 1 U/kg insulin (subcutaneous injection). Fasting blood glucose was measured weekly; plasma active GLP-1 was quantified via ELISA at day 14 [3]
- db/db mouse model (from [4]): Male db/db mice (8 weeks old, fasting blood glucose >300 mg/dL) were administered Alogliptin (1 mg/kg, dissolved in 0.5% methylcellulose) via oral gavage once daily for 28 days. Vehicle controls received 0.5% methylcellulose. HbA1c was measured at day 0 and 28; mice were euthanized on day 28, and pancreata were collected for β-cell mass quantification (hematoxylin-eosin staining) and plasma insulin assay [4]

Absorption, Distribution and Excretion
The pharmacokinetics of NESINA were similar in healthy subjects and patients with type 2 diabetes. Following a single oral dose of up to 800 mg in healthy subjects and patients with type 2 diabetes, peak plasma concentrations (median Tmax) of alogliptin occurred 1 to 2 hours after administration. Accumulation of alogliptin is extremely low. The absolute bioavailability of NESINA is approximately 100%. Food does not affect the absorption of alogliptin. Renal excretion (76%) and fecal excretion (13%) are observed. 60% to 71% of the dose is excreted unchanged in the urine. Following a single intravenous infusion of 12.5 mg alogliptin in healthy subjects, the terminal volume of distribution was 417 L, indicating good tissue distribution. Renal clearance was 9.6 L/h (indicating some active tubular secretion); systemic clearance was 14.0 L/h. The primary route of elimination for the radioactive material derived from alogliptin is renal excretion (76%), with an additional 13% recovered via feces, resulting in a total recovery of 89% of the administered dose. Renal clearance of alogliptin (9.6 L/hr) indicates some active tubular secretion, with a systemic clearance of 14.0 L/hr. Alogliptin is not extensively metabolized; 60% to 71% of the dose is excreted unchanged in the urine. The absolute bioavailability of NESINA is approximately 100%. Concomitant administration of NESINA with a high-fat meal does not significantly alter the total or peak exposure of alogliptin. Therefore, NESINA can be taken with or without food. In healthy subjects, a single intravenous infusion of 12.5 mg alogliptin resulted in a terminal volume of distribution of 417 L, indicating good tissue distribution. Alogliptin is 20% bound to plasma proteins. For more information on the absorption, distribution, and excretion (complete) of alogliptin (a total of 6 metabolites), please visit the HSDB record page. Metabolism/Metabolites Alogliptin is not extensively metabolized. The two minor metabolites detected were N-demethylated alogliptin (<1% of the parent compound) and N-acetylated alogliptin (<6% of the parent compound). The N-demethylated metabolite is active and is a DPP-4 inhibitor. The N-acetylated metabolite is inactive. The cytochrome enzymes involved in the metabolism of alogliptin are CYP2D6 and CYP3A4, but their metabolic extent is extremely low. Approximately 10-20% of the dose is metabolized by hepatic cytochrome enzymes. Two minor metabolites were detected after oral administration of [14C] alogliptin: N-demethylated metabolite MI (<1% of the parent compound) and N-acetylated metabolite M-II (<6% of the parent compound). MI is an active metabolite and, like the parent molecule, is a DPP-4 inhibitor; M-II has no inhibitory activity against DPP-4 or other DPP-related enzymes. In vitro data indicate that CYP2D6 and CYP3A4 are involved in the limited metabolism of alogliptin. Alogliptin exists primarily as the (R)-enantiomer (>99%), with little or no enantiomeric conversion to the (S)-enantiomer occurring in vivo. The (S)-enantiomer was not detected at a 25 mg dose.

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Biological Half-Life
Terminal Half-Life = 21 hours
At the maximum recommended clinical dose of 25 mg, the mean terminal half-life of nesinar is approximately 21 hours.

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In male Wistar rats: oral bioavailability of alogliptin was approximately 90% (oral 5 mg/kg vs. intravenous 1 mg/kg); intravenous administration showed a plasma elimination half-life (t₁/₂) of approximately 21 hours, an oral Cmax of 1.1 μg/mL (reached 2 hours after administration), and a volume of distribution (Vd) of approximately 4.5 L/kg [2]
-In beagle dogs: oral alogliptin (2 mg/kg) had a t₁/₂ of approximately 25 hours, an oral bioavailability of approximately 95%, and a plasma DPP-4 inhibition rate of >80% within 72 hours after administration [2]
-Metabolism: Alogliptin is minimally metabolized in rats and dogs (approximately 10% of the dose); metabolism is CYP-independent, and no active metabolites were detected [2]
- Excretion: In rats, approximately 75% of the intravenously administered dose was excreted unchanged in the urine within 72 hours, and approximately 15% was excreted in the feces [2]. Plasma protein binding: The protein binding of alogliptin in the plasma of rats and dogs was approximately 20% (ultrafiltration method) [2].

Toxicity Summary
Identification and Use: Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor indicated for use as adjunctive therapy to improve glycemic control in adults with type 2 diabetes; however, it is not indicated for the treatment of type 1 diabetes or diabetic ketoacidosis. Human Exposure and Toxicity: In clinical trials, adverse reactions reported by patients taking 25 mg alogliptin daily included pancreatitis (0.2%), hypersensitivity (0.6%), 1 case of serum sickness, nasopharyngitis (4.4%), hypoglycemia (1.5%), headache (4.2%), and upper respiratory tract infection (4.2%). The incidence of hypoglycemia increased to 5.4% in elderly patients taking alogliptin. Post-marketing, patients taking alogliptin reported acute pancreatitis and serious hypersensitivity reactions. These reactions included anaphylactic reactions, angioedema, and serious skin adverse reactions, including Stevens-Johnson syndrome. Post-marketing reports have shown fatal and non-fatal hepatic failure in patients taking nesina. Animal studies: In a rat fertility study, alogliptin at doses up to 500 mg/kg (approximately 172 times the clinical dose based on plasma drug exposure (AUC)) did not have adverse effects on early embryonic development, mating, or fertility. During organogenesis, administration of alogliptin to pregnant rabbits and rats at doses up to 200 mg/kg and 500 mg/kg (approximately 149 times and 180 times the clinical dose based on plasma drug exposure (AUC), respectively), did not reveal teratogenicity. From day 6 of gestation to day 20 of lactation, administration of alogliptin at doses up to 250 mg/kg (approximately 95 times the clinical exposure based on AUC) to pregnant rats did not harm the developing embryo or adversely affect the growth and development of offspring. Following oral administration to pregnant rats, alogliptin was observed to be transplacentally transported to the fetus. The ratio of alogliptin concentration in lactating rat milk to plasma concentration was 2:1. Mice were administered alogliptin at doses of 50, 150, or 300 mg/kg for two consecutive years (approximately 51 times the maximum recommended clinical dose of 25 mg based on AUC exposure), and no drug-related tumors were observed. In Ames tests against Salmonella and Escherichia coli, and in cytogenetic assays of mouse lymphoma cells, alogliptin did not exhibit mutagenicity or chromosome breakage, regardless of metabolic activation. In in vivo mouse micronucleus studies, alogliptin was negative.
Hepatotoxicity
Liver injury caused by alogliptin is rare. In large clinical trials, elevated serum enzymes were uncommon (1% to 3%) and not higher than in the control or placebo groups. No cases of clinically significant liver injury with jaundice were reported in these studies. Since its market launch, the FDA and sponsor have received reports of elevated serum enzymes and acute hepatitis (including acute liver failure) caused by alogliptin. These cases have not been reported in the literature, and their clinical characteristics are not well-defined. Other DPP-4 inhibitors (such as sitagliptin and saxagliptin) have been reported to cause clinically significant acute liver injury. The latency period for liver injury is typically 2 to 12 weeks after medication, and the pattern of elevated liver enzymes is usually hepatocellular. Immune allergic reactions are common. Most cases resolve spontaneously, with symptoms rapidly reversing upon discontinuation of the drug.
Probability Score: E (Unproven but suspected cause of acute specific liver injury).

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Effects during Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information on the clinical use of alogliptin during lactation. Alternative medications are recommended, especially for breastfed newborns or premature infants. Monitoring of blood glucose levels in breastfed infants is recommended while the mother is receiving alogliptin treatment.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Lactation and Breast Milk
No published information found as of the revision date. Protein Binding: Alogliptin binds to plasma proteins in 20% of its volume. Drug Interactions: Compared to sulfonylurea or insulin monotherapy, the incidence of hypoglycemia increases when alogliptin is used in combination with insulin secretagogues (such as sulfonylureas) or insulin. Therefore, patients receiving alogliptin may need to reduce the dose of the concurrent insulin secretagogue or insulin to decrease the risk of hypoglycemia.

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In rats and dogs (28-day repeated-dose studies): Oral administration of alogliptin at doses up to 50 mg/kg/day (rat) and 20 mg/kg/day (dog) did not cause significant weight loss, hepatotoxicity (no change in serum ALT/AST), or nephrotoxicity (normal creatinine/BUN); no histopathological abnormalities were observed in the liver, kidneys, or pancreas [2,3]
-In db/db mice and STZ-induced diabetic rats (treatment doses: oral administration of 1–3 mg/kg/day for 14–28 days): no significant adverse reactions were observed (e.g., gastrointestinal symptoms, hypoglycemia); peripheral blood cell counts remained within the normal range [3,4]
-In human hepatocytes, MIN6 cells, and rat islets: treatment with up to 20 μM alogliptin for 72 hours did not show significant cytotoxicity (cell viability >90% vs. solvent control group, MTT assay) [2,3,4]

[1]. J Pharmacol Toxicol Methods . 2015 Jan-Feb:71:8-12.

[2]. J Med Chem . 2007 May 17;50(10):2297-300.

[3]. Eur J Pharmacol . 2008 Jul 28;589(1-3):306-14.

[4]. Eur J Pharmacol . 2008 Jul 7;588(2-3):325-32.

Alogliptin is a piperidine compound, chemically named 3-methyl-2,4-dioxo-3,4-dihydropyrimidine, with a 2-cyanobenzyl group and a 3-aminopiperidin-1-yl group (R-enantiomer) linked at positions 1 and 2, respectively. It is used in benzoate form to treat type 2 diabetes. Alogliptin is a dipeptidyl peptidase IV (DPP-4) inhibitor (EC 3.4.14.5) and also a hypoglycemic agent. It is a nitrile compound belonging to the piperidine, pyrimidine, and primary amino groups. It is the conjugate base of alogliptin (1+). Alogliptin is a selective, orally bioavailable inhibitor of dipeptidyl peptidase-4 (DPP-4) enzyme activity. Alogliptin is prepared in benzoate form, primarily in the R-enantiomer (>99%). Alogliptin undergoes almost no chiral conversion in vivo to form the (S)-enantiomer. The U.S. Food and Drug Administration (FDA) approved it for marketing on January 25, 2013. Alogliptin is a dipeptidyl peptidase-4 (DPP-4) inhibitor. Its mechanism of action is as a DPP-4 inhibitor. Alogliptin is a DPP-4 inhibitor that can be used in combination with diet and exercise to treat type 2 diabetes, either alone or in combination with other oral hypoglycemic agents. There are reports of alogliptin causing liver damage, but the characteristics and details of this damage have not been clearly defined in published literature. Alogliptin is a selective, orally bioavailable pyrimidine diketone DPP-4 inhibitor with hypoglycemic activity. In addition to its effect on blood glucose levels, alogliptin may also suppress inflammatory responses by inhibiting the production of pro-inflammatory cytokines mediated by Toll-like receptor 4 (TLR-4). See also: Alogliptin benzoate (salt form); Alogliptin; Metformin hydrochloride (ingredient).

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Drug Indications
Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.

FDA Label

Vipidia is indicated for use in combination with other hypoglycemic agents (including insulin) to improve glycemic control, particularly when diet and exercise combined with other hypoglycemic agents do not provide adequate glycemic control (see Sections 4.4, 4.5, and 5.1 for available data on different combinations).

Treatment of Type 2 Diabetes
Mechanism of Action
Alogliptin inhibits dipeptidyl peptidase-4 (DPP-4), which normally degrades incretins, including glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1). Inhibition of DPP-4 increases the level of active incretins in the plasma, thereby contributing to glycemic control. GIP and GLP-1 stimulate the secretion of glucose-dependent insulin by pancreatic β-cells.
GLP-1 also inhibits glucose-dependent glucagon secretion, induces satiety, reduces food intake, and delays gastric emptying. After eating, the small intestine releases incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) into the bloodstream, where their concentrations increase. These hormones stimulate pancreatic β-cells to release insulin in a glucose-dependent manner, but are inactivated by the DPP-4 enzyme within minutes. GLP-1 also reduces glucagon secretion from pancreatic α-cells, thereby reducing hepatic glucose production. In patients with type 2 diabetes, GLP-1 concentrations are reduced, but the insulin response to GLP-1 remains. Alogliptin is a DPP-4 inhibitor that slows the inactivation of incretin hormones, thereby increasing their blood concentrations and lowering fasting and postprandial blood glucose levels in patients with type 2 diabetes in a glucose-dependent manner. In vitro, at concentrations close to therapeutic exposure, alogliptin selectively binds to and inhibits the activity of DPP-4, but does not inhibit the activity of DPP-8 or DPP-9.

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Therapeutic Use
Hydroxyglycemic Agents
Nesina is indicated in a variety of clinical settings as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. /US Product Label Includes/
A single-dose, open-label study evaluated the pharmacokinetics of 50 mg alogliptin in patients with chronic renal impairment and healthy subjects. An approximately 1.2-fold increase in plasma AUC of alogliptin was observed in patients with mild renal impairment (creatinine clearance (CrCl) = 60 to < 90 mL/min). Because this increase is not clinically significant, dose adjustment is not recommended for patients with mild renal impairment. An approximately 2-fold increase in plasma AUC of alogliptin was observed in patients with moderate renal impairment (CrCl = 30 to < 60 mL/min). To ensure systemic exposure to nesina is similar to that in patients with normal renal function, a dose of 12.5 mg once daily is recommended for patients with moderate renal impairment. In patients with severe renal impairment (CrCl = 15 to < 30 mL/min) and end-stage renal disease (ESRD, CrCl < 15 mL/min or requiring dialysis), an increase in plasma AUC of alogliptin was observed to be approximately 3-fold and 4-fold, respectively. Dialysis removes approximately 7% of the drug during a 3-hour dialysis session. Dialysis time is not a consideration when taking Nesina. To ensure similar systemic exposure to Nesina as in patients with normal renal function, the recommended dose for patients with severe renal impairment and those with end-stage renal disease (ESRD) requiring dialysis is 6.25 mg once daily.

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Drug Warning
/Black Box Warning/ Warning: Risk of Lactic Acidosis. Lactic acidosis is a rare but serious complication that can be caused by metformin accumulation. The risk is increased in cases of renal impairment, sepsis, dehydration, excessive alcohol consumption, hepatic impairment, and acute congestive heart failure. The onset is usually insidious, with only nonspecific symptoms such as malaise, myalgia, dyspnea, increased drowsiness, and nonspecific abdominal discomfort. Abnormal laboratory findings include decreased pH, increased anion gap, and elevated blood lactate levels. If acidosis is suspected, cazapro (a combination of alogliptin and metformin hydrochloride) should be discontinued immediately, and the patient should be taken to a hospital. /Alogliptin and metformin hydrochloride combination/
The U.S. Food and Drug Administration (FDA) is evaluating new, unpublished findings from a group of academic researchers that suggest an increased risk of pancreatitis and a precancerous cellular lesion called pancreatic duct metaplasia in patients with type 2 diabetes treated with a class of drugs called incretin analogs. These findings are based on examination of pancreatic tissue samples from a small number of post-mortem patients whose cause of death is unknown. The FDA has requested that researchers provide methods for collecting and studying these samples, as well as tissue samples, so that the FDA can further investigate the potential pancreatic toxicity associated with incretin analogs. Incretin analogues include exenatide (Byetta, Baidu Ruian), liraglutide (Vituzar), sitagliptin (Jenova, Genomex, Genomex Extended Release, Uvitine), saxagliptin (Amligiz, Combigliza Extended Release), alogliptin (Nesina, Kazzano, Osenib), and linagliptin (Trajeta, Gentaduto). These drugs work by mimicking the body's naturally produced incretin hormones, stimulating the release of insulin after meals. They are used in conjunction with diet and exercise to lower blood sugar in adults with type 2 diabetes. The FDA has not yet reached any new conclusions regarding the safety risks of incretin analogues. This preliminary notification is intended only to inform the public and healthcare professionals, and the FDA plans to obtain and evaluate this new information. …The FDA will release its final conclusions and recommendations after completing its review or obtaining more information. The "Warnings and Precautions" section of the drug labels and patient guides for incretin analogues contains warnings about the risk of acute pancreatitis. The FDA has not previously released any information regarding the risk that incretin analogues may cause precancerous lesions of the pancreas. The FDA has not concluded that these drugs may cause or promote pancreatic cancer. Currently, patients should continue to take the medication as prescribed until they consult a healthcare professional; healthcare professionals should also continue to follow the prescribing advice on the drug label. ...
Post-marketing reports indicate fatal and non-fatal liver failure in patients taking Nesina, but some reports lack sufficient information to determine the possible cause.
Post-marketing reports indicate serious hypersensitivity reactions in patients receiving Nesina. These reactions included anaphylactic shock, angioedema, and severe skin adverse reactions, including Stevens-Johnson syndrome. If a serious hypersensitivity reaction is suspected, Nesina should be discontinued, other possible causes of the event evaluated, and alternative diabetes treatment options considered.
For more complete data on drug warnings for alogliptin (18 in total), please visit the HSDB records page.

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Pharmacodynamics
In healthy subjects, peak DPP-4 inhibition is achieved within 2–3 hours after a single dose. Peak DPP-4 inhibition exceeds 93% across a dose range of 12.5 mg to 800 mg. For doses ≥25 mg, DPP-4 inhibition remains above 80% after 24 hours. Compared to placebo, alogliptin reduces postprandial glucagon levels and increases postprandial active GLP-1 levels within 8 hours after a standard meal. Alogliptin does not affect the QTc interval.

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Alogliptin (SYR322) is an oral, long-acting DPP-4 inhibitor approved by the FDA in 2010 for the treatment of type 2 diabetes mellitus (T2DM), including patients with renal insufficiency (due to minimal metabolism and renal excretion, no dose adjustment is required) [2,4]
- Its mechanism of action is irreversible binding to DPP-4, inhibiting the degradation of incretins (GLP-1 and GIP), thereby enhancing glucose-dependent insulin secretion, inhibiting glucagon release, and maintaining the number of pancreatic β cells [2,3]
- Preclinical studies have shown that alogliptin has a long-acting effect (once-daily dosing) and a synergistic hypoglycemic effect when used in combination with insulin or metformin, thus making it suitable for combination therapy [3,4]
- Due to its non-CYP-dependent metabolism and low plasma protein binding rate (approximately 20%), the risk of drug interactions with alogliptin is low [2]

C18H21N5O2

339.391643285751

339.17

C, 63.70; H, 6.24; N, 20.64; O, 9.43

850649-61-5

Alogliptin Benzoate;850649-62-6;Alogliptin-d3;1133421-35-8;Alogliptin-13C,d3 benzoate;Alogliptin-13C,d3;1246817-18-4

11450633

White to off-white solid powder

1.3±0.1 g/cm3

519.2±60.0 °C at 760 mmHg

267.8±32.9 °C

0.0±1.4 mmHg at 25°C

1.66

0.6

1

5

3

25

622

1

CN1C(=O)C=C(N(C1=O)CC2=CC=CC=C2C#N)N3CCC[C@H](C3)N

ZSBOMTDTBDDKMP-OAHLLOKOSA-N

InChI=1S/C18H21N5O2/c1-21-17(24)9-16(22-8-4-7-15(20)12-22)23(18(21)25)11-14-6-3-2-5-13(14)10-19/h2-3,5-6,9,15H,4,7-8,11-12,20H2,1H3/t15-/m1/s1

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxopyrimidin-1-yl]methyl]benzonitrile

SYR 322; Alogliptin; SYR-322; 850649-61-5; alogliptina; (R)-2-((6-(3-aminopiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)benzonitrile; Alogliptin [INN]; UNII-JHC049LO86; alogliptine; alogliptinum; SYR322; Brand name: Nesina; Kazano; Oseni

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (7.37 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 0.5% methylcellulose: 30 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)