SPH3127 (DRI 18) is a new, potent, orally bioactive direct renin inhibitor (recombinant human-renin IC50=0.4 nM, human plasma renin activity IC50=0.45 nM). SPH3127 has anti-hypertensive (blood pressure lowering) effects and may be utilized in the research/study of hypertension.

Physicochemical Properties

Molecular Formula	C22H32N6O4
Molecular Weight	444.53
Exact Mass	444.248
CAS #	1399849-02-5
Related CAS #	2102663-60-3 (malate);1399849-02-5;
PubChem CID	117877477
Appearance	Off-white to pink solid powder
LogP	0.8
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	9
Heavy Atom Count	32
Complexity	662
Defined Atom Stereocenter Count	2
SMILES	C1(CC1)N(C([C@H]1CNCCO1)=O)[C@H](C)C1C2=C(N(N=1)CCCNC(=O)OC)N=C(C=C2)C
InChi Key	GRTDDIZIUSADLD-CRAIPNDOSA-N
InChi Code	InChI=1S/C22H32N6O4/c1-14-5-8-17-19(26-27(20(17)25-14)11-4-9-24-22(30)31-3)15(2)28(16-6-7-16)21(29)18-13-23-10-12-32-18/h5,8,15-16,18,23H,4,6-7,9-13H2,1-3H3,(H,24,30)/t15-,18-/m1/s1
Chemical Name	methyl N-[3-[3-[(1R)-1-[cyclopropyl-[(2R)-morpholine-2-carbonyl]amino]ethyl]-6-methylpyrazolo[3,4-b]pyridin-1-yl]propyl]carbamate
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vivo	SPH3127 (oral; 0-10 mg/kg; once) showed good absorption in cynomolgus monkeys [1]. SPH3127 (orally; 0-3 mg/kg; once) showed antihypertensive effects in Tsukuba hypertensive mice [1].
Animal Protocol	Animal/Disease Models: Cynomolgus monkeys were pretreated with a low-sodium diet and furosemide [1] Doses: 0, 1, 3, 10 mg/kg Route of Administration: po (po (oral gavage)) 1, 3 and 10 mg/kg; Experimental Results: inhibit plasma renin activity, IC50 value is 0.46 nM, and have blood pressure lowering effect. Animal/Disease Models: Tsukuba hypertensive mouse (THM) [1] Doses: 0, 0.3, 1 or 3 mg/kg Route of Administration: oral; Route of Administration: oral. 0, 0.3, 1 or 3 mg/kg; Experimental Results: 0.3~3mg/kg demonstrated a dose-dependent antihypertensive effect on Tsukuba hypertensive mice, and the maximum antihypertensive effect 2~3h after any dose was administered was about 30mmHg.
References	[1]. Discovery of SPH3127: A Novel, Highly Potent, and Orally Active Direct Renin Inhibitor. J Med Chem. 2022 Aug 8.

Solubility Data

Solubility (In Vitro)

DMSO : ~100 mg/mL (~224.96 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 5 mg/mL (11.25 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 50.0 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. Solubility in Formulation 2: ≥ 5 mg/mL (11.25 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 50.0 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. Solubility in Formulation 3: ≥ 5 mg/mL (11.25 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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.2496 mL	11.2478 mL	22.4957 mL
	5 mM	0.4499 mL	2.2496 mL	4.4991 mL
	10 mM	0.2250 mL	1.1248 mL	2.2496 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.