DPP-4 (IC50 = 1.6 nM)

Omarigliptin is a potent DPP-4 inhibitor with weak ion channel activity (IC50 > 30 μmol/L at IKr, Caγ1.2, and Naγ1.5) and strong selectivity over other proteases tested (IC50 > 67 μmol/L). Furthermore, in every assay within an extensive selectivity counterscreen comprising 168 radioligand binding or enzymatic assays, an IC50 > 10 μmol/L was achieved. Under hyperglycemic circumstances, omagliptin binds quickly and competitively to the DPP-4 active site, a reversible and highly selective process that raises insulin levels and lowers glucagon levels[2].

In an oral glucose tolerance test (OGTT), it was given orally to lean mice one hour before the dextrose challenge. It significantly decreased blood glucose excursion in a dose-dependent manner, going from 0.01 mg/kg (7% reduction in glucose AUC) to 0.3 mg/kg (51% reduction). Plasma concentrations of active GLP-1 are dose-dependently increased upon omarigliptin administration. The male Sprague-Dawley rat and beagle dog exhibit low plasma clearance (0.9−1.1 mL/min/kg), 0.8−1.3 L/kg at steady state for the volume of distribution, and a long terminal half-life (∼11−22 h) in relation to the pharmacokinetics of omarigliptin. Omaligliptin has a good oral bioavailability in both dogs and rats (approximately 100%). Throughout the course of the trial, omajiptin is well tolerated; no death or adverse physical symptoms are observed[1]. After volunteers received a single oral dose of 25 mg, omarigliptin was absorbed quickly, reaching peak concentrations (Cmax) of 750 nmol/L in less than one hour (Tmax). The estimated bioavailability was 74%[2].

Omarigliptin is a potent DPP-4 inhibitor with weak ion channel activity (IC50 > 30 μmol/L at IKr, Caγ1.2, and Naγ1.5) and strong selectivity over other proteases tested (IC50 > 67 μmol/L). Furthermore, in every assay within an extensive selectivity counterscreen comprising 168 radioligand binding or enzymatic assays, an IC50 > 10 μmol/L was achieved. Under hyperglycemic circumstances, omagliptin binds quickly and competitively to the DPP-4 active site, a reversible and highly selective process that raises insulin levels and lowers glucagon levels.

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In Vitro Pharmacology[1]
Omarigliptin is a competitive, reversible inhibitor of DPP-4 (IC50 = 1.6 nM, Ki = 0.8 nM) and is more potent than sitagliptin (IC50 = 18 nM). It is highly selective over all proteases tested (IC50 > 67 μM), including QPP, FAP, PEP, DPP8, and DPP9. The compound has weak ion channel activity (IC50 > 30 μM at IKr, Cav1.2, and Nav1.5). An expansive selectivity counterscreen (168 radioligand binding or enzymatic assays) was carried out at MDS Pharma. An IC50 > 10 μM was obtained in all assays.

12 weeks, C57BL/6 male mice
2.5, 5 mg/kg
P.o.; once a week for 8 weeks (50 mg/kg streptozotocin (STZ); i.p.; daily for five days)

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In Vivo Pharmacology in Preclinical Species[1]
Omarigliptin was evaluated for its ability to improve glucose tolerance in lean mice. When orally administered 1 h prior to dextrose challenge in an oral glucose tolerance test (OGTT), it significantly reduced blood glucose excursion in a dose-dependent manner from 0.01 mg/kg (7% reduction in glucose AUC) to 0.3 mg/kg (51% reduction). The efficacy of glucose lowering in this model was similar to that achieved with sitagliptin. In the corresponding pharmacodynamic (PD) assay, omarigliptin-mediated plasma DPP-4 inhibition and plasma compound concentrations were dose-dependent. At the 0.3 mg/kg dose (corresponding to maximum acute glucose lowering efficacy), plasma DPP-4 activity was inhibited by 85% (uncorrected for assay dilution), which exceeds the target inhibition (80%) associated with maximal glucose lowering efficacy. The observed plasma DPP-4 inhibition was consistent with the measured plasma inhibitor concentration (521 nM) and the potency of the compound against murine plasma DPP-4 (IC50 = 43.9 nM in 50% mouse plasma). In addition, the administration of omarigliptin dose-dependently increased plasma concentrations of active GLP-1 (GLP-1[7–36]amide and GLP-1[7–37]) in this study, with the maximal increase in active GLP-1 observed at the 0.3–1 mg/kg dosages. The augmentation of active GLP-1 levels achieved at these doses (>10-fold) was in the range of elevation in circulating hormone observed in DPP-4-deficient (Dpp4–/–) mice (3- to 8-fold) relative to wild type animals

Pharmacokinetics (PK) in Preclinical Species[1]
PK experiments were generally conducted as follows: All species were fasted overnight before dosing, provided water ad libitum, and fed 4 h following drug treatment. Blood was collected at predetermined intervals for all species into EDTA-containing tubes and centrifuged. Plasma was harvested and stored at −70 °C until analysis.

Test compounds were typically formulated as solutions in saline. Fasted male Sprague–Dawley rats were given either an iv dose of test compound solution via a cannula implanted in the femoral vein (n = 2) or a po dose by gavage (n = 3). Serial blood samples were collected at 5 (iv only), 15, and 30 min and at 1, 2, 4, 6, 8, 24, and 48 h postdose. Plasma was collected by centrifugation, and plasma concentrations of test compound were determined by LC–MS/MS following protein precipitation with acetonitrile.

Fasted dogs were administered intravenous doses via the cephalic vein (dogs, n = 2). Oral doses were administered via gastric gavage (n = 2). Serial blood samples were collected at 5 (iv only), 15, and 30 min and at 1, 2, 4, 6, 8, 24, 30, 48, and 72 h postdose. Plasma was collected by centrifugation, and plasma concentrations of test compound were determined by LC–MS/MS following protein precipitation with acetonitrile. Pharmacokinetic parameters were calculated by established noncompartmental methods.

The pharmacokinetics of omarigliptin in male Sprague–Dawley rat and beagle dog were characterized by a low plasma clearance (0.9–1.1 mL min–1 kg–1), a volume of distribution at steady state of 0.8–1.3 L/kg, and a long terminal half-life (∼11–22 h) (Table 1). The oral bioavailability of omarigliptin was good in both dogs and rats (∼100%). The mean percentage of unbound [3H]omarigliptin (1, 10, and 100 μM) in CD-1 mouse, Sprague–Dawley rat, beagle dog, and human plasma was 38%, 15%, 43%, and 68%, respectively. The blood-to-plasma concentration ratio in these species ranged from 0.6 to 1.2.

Omarigliptin has a long half-life (rat, 11 h; dog, 22 h) and lower clearance (rat, 1.1 mL min–1 kg–1; dog, 0.9 mL min–1 kg–1) in preclinical species. On the basis of the human PK prediction, omarigliptin is projected to be amenable for once-weekly dosing. This is recapitulated in the clinical studies, where omarigliptin is shown to have a biphasic PK profile with a terminal half-life of 120 h.

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Pharmaceutical Properties[1]
Omarigliptin used for clinical trial is a white material. Crystallinity was confirmed by optical microscopy and XRPD. Differential scanning calorimetry (DSC) showed a melting endotherm at 176.0 °C (heat of fusion, 89.68 J/g). The glass transition temperature of the amorphous material was found to be 58 °C. An anhydrous crystalline free base of omarigliptin is chemically and physically stable at 40 °C/75% RH for up to 4 weeks. Omarigliptin was shown to be photostable as a bulk material under 100 000 lx·h of cool white fluorescent light.[1]
After a 24 h equilibration in aqueous buffer, the concentration of omarigliptin is 7.1 mg/mL (pH 2), 8.7 mg/mL (pH 6), and 3.1 mg/mL (pH 8). After a 24 h equilibration of omarigliptin in buffer, the concentration of omarigliptin was >20 mg/mL (pH 2–6) and 6.2 mg/mL at pH 8. Omarigliptin has two pKa values measured at 3.5 and 7.1.

Omarigliptin is negative in the Ames mutagenicity assay.[1]
In the PatchXpress cardiac ion channel panel, omarigliptin exhibited minimal functional inhibition of hERG current up to the highest tested concentration of 30 μM. In the nonfunctional MK-499 displacement binding studies the compound had an IC50 of >30 μM, and there were no remarkable effects on IKs, INa, and ICaL up to 30 μM.[1]
Omarigliptin was also evaluated in an exploratory 14-day oral safety study in male rats at 100 mg kg–1 day–1. The compound was well tolerated over the duration of the study, with no mortality or physical signs noted. Clinical pathology findings were limited to slight decreases in glucose, triglycerides, and cholesterol. The AUC(0–24h), Cmax, and Tmax were 5003 μM·h, 371 μM, and 2 h, respectively.

[1]. J Med Chem . 2014 Apr 24;57(8):3205-12.

[2]. Drugs . 2015 Nov;75(16):1947-52.

Omarigliptin is a pyrrolopyrazole.
Omarigliptin has been used in trials studying the treatment of Type 2 Diabetes Mellitus and Chronic Renal Insufficiency.

C17H20F2N4O3S

398.43

398.122

C, 51.25; H, 5.06; F, 9.54; N, 14.06; O, 12.05; S, 8.05

1226781-44-7

46209133

White to off-white solid powder

1.6±0.1 g/cm3

529.4±60.0 °C at 760 mmHg

274.0±32.9 °C

0.0±1.4 mmHg at 25°C

1.689

0.46

1

8

3

27

649

3

S(C([H])([H])[H])(N1C([H])=C2C(C([H])([H])N(C2([H])[H])[C@@]2([H])C([H])([H])O[C@]([H])(C3C([H])=C(C([H])=C([H])C=3F)F)[C@]([H])(C2([H])[H])N([H])[H])=N1)(=O)=O

MKMPWKUAHLTIBJ-ISTRZQFTSA-N

InChI=1S/C17H20F2N4O3S/c1-27(24,25)23-7-10-6-22(8-16(10)21-23)12-5-15(20)17(26-9-12)13-4-11(18)2-3-14(13)19/h2-4,7,12,15,17H,5-6,8-9,20H2,1H3/t12-,15+,17-/m1/s1

(2R,3S,5R)-2-(2,5-difluorophenyl)-5-(2-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazol-5-yl)oxan-3-amine

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 (6.27 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 (6.27 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 (6.27 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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 (Please use freshly prepared in vivo formulations for optimal results.)