CI-1044 is a novel, potent and orally bioavailable PDE4 (phosphodiesterase 4) inhibitor with IC50s of 0.29, 0.08, 0.56, 0.09 μM for PDE4A5, PDE4B2, PDE4C2 and PDE4D3, respectively. It inhibits LPS-induced TNF-alpha production in whole blood in chronic obstructive pulmonary disease (COPD) patients.

Physicochemical Properties

Molecular Formula	C23H19N5O2
Molecular Weight	397.429264307022
Exact Mass	397.153
CAS #	197894-84-1
PubChem CID	9843744
Appearance	Light yellow to yellow solid powder
Density	1.4±0.1 g/cm3
Boiling Point	773.2±60.0 °C at 760 mmHg
Flash Point	421.4±32.9 °C
Vapour Pressure	0.0±2.6 mmHg at 25°C
Index of Refraction	1.750
LogP	0.3
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	3
Heavy Atom Count	30
Complexity	704
Defined Atom Stereocenter Count	1
SMILES	C1CN2C(=O)[C@@H](N=C(C3=CC(=CC1=C32)N)C4=CC=CC=C4)NC(=O)C5=CN=CC=C5
InChi Key	XGXOSJSGDNPEEF-NRFANRHFSA-N
InChi Code	InChI=1S/C23H19N5O2/c24-17-11-15-8-10-28-20(15)18(12-17)19(14-5-2-1-3-6-14)26-21(23(28)30)27-22(29)16-7-4-9-25-13-16/h1-7,9,11-13,21H,8,10,24H2,(H,27,29)/t21-/m0/s1
Chemical Name	(R)-N-(9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)nicotinamide
Synonyms	PD-189659; PD 189659; PD189659; CI-1044; CI 1044; CI1044; UNII-O4T475XIIY.
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
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 Vitro	CI-1044 is an orally active PDE4 inhibitor having IC50s of 0.29, 0.08, 0.56, and 0.09 μM for PDE4A5, PDE4B2, PDE4C2, and PDE4D3, respectively. CI-1044 selectively inhibits crude extracts of PDE4 in U937 cells with an IC50 value of 0.27±0.02 μM, which is three times more potent than rolipram (IC50=0.91±0.14) and than cillast (IC50= 0.026±0.007) ten times lower. In the presence of PDE4 inhibitors, TNF-α production decreased in a dose-dependent manner, with average IC50 values of 0.31±0.05 and 0.26±0.05 from three independent trials for CI-1044, cillast and rolipram, respectively. and 0.11±0.01 μM. 1].
ln Vivo	Following a solitary oral dosage, TNF-α production was dose-dependently inhibited by CI-1044, rolipram, and cilomilast, with respective ID50 values of 0.4, 1.4, and 1.6 mg/kg. Following multiple oral doses of CI-1044, the ID50 value is equivalent to 0.5 mg/kg. The concentrations of CI-1044 in plasma rose in a proportionate manner within the dose range of 0.1 to 40 mg/kg po (R2=0.878). With an ID50 value of 3.25 mg/kg, CI-1044 dose-dependently inhibits the accumulation of eosinophils in bronchoalveolar lavage (BAL) fluid. A single dose of CI-1044 (10 mg/kg, po) administered 24, 8, 3, or 1 hour prior to the antigen challenge resulted in a 6%, 56%, 48%, and 79% suppression of BAL eosinophil counts [1].
References	[1]. Relationship between phosphodiesterase type 4 inhibition and anti-inflammatory activity of CI-1044 in rat airways. Fundam Clin Pharmacol. 2010 Feb;24(1):73-82.

Solubility Data

Solubility (In Vitro)

DMSO : ~125 mg/mL (~314.52 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (5.23 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 20.8 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: ≥ 2.08 mg/mL (5.23 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 20.8 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.5162 mL	12.5808 mL	25.1617 mL
	5 mM	0.5032 mL	2.5162 mL	5.0323 mL
	10 mM	0.2516 mL	1.2581 mL	2.5162 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.