Dolutegravir

Category	HIV Integrase
CAS	1051375-16-6
Description	Dolutegravir is a two-metal-binding HIV-1 integrase inhibitor with IC50 of 2.7 nM, with modest activity against raltegravir-resistant signature mutants Y143R, Q148K, N155H, and G140S/Q148H. It blocks the strand transfer step of the integration of the viral genome into the host cell (INSTI).

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Product Information

Synonyms	GSK-1349572; GSK 1349572; GSK1349572; Tivicay
Molecular Weight	419.38
Molecular Formula	C20H19F2N3O5
Canonical SMILES	CC1CCOC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)O
InChI	InChI=1S/C20H19F2N3O5/c1-10-4-5-30-15-9-24-8-13(17(26)18(27)16(24)20(29)25(10)15)19(28)23-7-11-2-3-12(21)6-14(11)22/h2-3,6,8,10,15,27H,4-5,7,9H2,1H3,(H,23,28)/t10-,15+/m1/s1
InChIKey	RHWKPHLQXYSBKR-BMIGLBTASA-N
Boiling Point	669.0±55.0 °C at 760 mmHg
Flash Point	358.4±31.5 °C
Purity	≥98%
Density	1.53 g/cm3
Solubility	In Vitro: DMSO : 10 mg/mL(23.84 mM;Need ultrasonic and warming) In Vivo: 1.Add each solvent one by one:5% DMSO >> 95% (20%SBE-β-CDin saline) Solubility: ≥ 2.62 mg/mL (6.25 mM); Clear solution 2.Add each solvent one by one:10% DMSO >> 40%PEG300 >> 5%Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (5.96 mM); Clear solution 3.Add each solvent one by one:10% DMSO >> 90% (20%SBE-β-CDin saline) Solubility: ≥ 2.5 mg/mL (5.96 mM); Clear solution 4.Add each solvent one by one:10% DMSO >> 90%corn oil Solubility: ≥ 2.5 mg/mL (5.96 mM); Clear solution
Appearance	White to off-white (Solid)
Storage	2-8°C
Animal Admin	For rat and monkey PK studies, Dolutegravir is administered in the form of free acid or sodium salts. All doses are expressed as free acid. Dolutegravir is administered to three male rats and two male monkeys by intravenous (IV) short-term (within 2 min) bolus (1 mg/kg). For a single oral administration, Dolutegravir is administered as a solution (5 mg/kg) to three fasted male rats and two fasted male monkeys. Dolutegravir is administered to non-fasted male rats (n=2/dose level) and 3, 10 and 50 mg/kg to non-fasting female monkeys at a single oral dose of 5, 50, 100 and 250 mg/kg. For intravenous administration, blood samples are collected from rats (0.2 mL through jugular vein cannula) and monkeys (approximately 0.2 or 0.5 mL through the great saphenous vein of hindlimbs) into 0.02, 0.25, 0.5, 1, 2, 4 Na2EDTA-treated syringes for 6, 8 and 24 h. For oral administration, samples are collected at 0.25 (rats only), 0.5, 1, 2, 4, 6 [rats (solution and suspension) and monkeys (solution only)], 8 and 24 h. Immediately after collection, the blood is placed on wet ice and then centrifuged at 1740 g for 10 min over 1 h and at 4 °C to obtain plasma. Prior to analysis, store all samples at approximately -20 °C or colder temperatures by using methods based on protein precipitation and LC-MS/MS analysis.
Complexity	829
Exact Mass	419.12927704
Index Of Refraction	1.650
In Vitro	Dolutegravir (S/GSK1349572) has an EC50 of 0.51 nM for HIV-1 in PBMCs, 0.71 nM in MT-4 cells, and 2.2 nM in PHIV assays, which use pseudotype autoinactivation of the virus. Dolutegravir has 50% cytotoxic concentrations (CC50) of 4.8, 7.0, 14 and 15 μM in proliferating IM-9, U-937, MT-4, and Molt-4 cells, respectively. In unstimulated and stimulated PBMCs, CC50s are 189 μM and 52 μM, respectively. Based on Dolutegravir's EC50 (i.e., 0.51 nM) for HIV-1 in PBMCs, this translates into a cell-based therapeutic index of at least 9,400.
In Vivo	After a single intravenous (IV) administration of Dolutegravir, plasma clearance is low in rats (0.23 mL/min/kg) and monkeys (2.12 mL/min/kg). The half-life of rats and monkeys is similar, about 6 hours, and the steady-state volume of distribution (VSS) is low. After oral administration, when administered as a solution for fasting male rats and single monkeys, Dolutegravir is rapidly absorbed with high oral bioavailability (75.6% and 87.0%, respectively). Dolutegravir exposure (Cmax and AUC) increases with increasing dose, with oral administration of 250 mg/kg in non-fasted rats and up to 50 mg/kg in non-fasting monkeys, although the increase is less than proportional.
PSA	104.36000
Target	HIV Integrase; HIV
Vapor Pressure	0.0±2.1 mmHg at 25°C
XLogP3-AA	2.4