Brensocatib (formerly known as AZD-7986; INS-1007) is a novel, second generation, highly potent, covalent reversible, and selective DPP1 (Dipeptidyl peptidase 1) inhibitor with anti-COPD effects. It inhibits DPP1 with pIC50s of 6.85, 7.6, 7.7, 7.8, and 7.8 in human, mouse, rat, dog and rabbit, respectively. It is free from aorta binding liabilities found for earlier compound series and has the potential for treating COPD (chronic obstructive pulmonary disease) with predicted human PK properties suitable for once daily human dosing.

Physicochemical Properties

Molecular Formula	C23H24N4O4
Molecular Weight	420.47
Exact Mass	420.18
CAS #	1802148-05-5
Related CAS #	1802148-05-5
PubChem CID	118253852
Appearance	Light yellow to yellow solid powder
LogP	2.447
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	5
Heavy Atom Count	31
Complexity	699
Defined Atom Stereocenter Count	2
SMILES	CN1C2=C(C=CC(=C2)C3=CC=C(C=C3)C[C@@H](C#N)NC(=O)[C@@H]4CNCCCO4)OC1=O
InChi Key	AEXFXNFMSAAELR-RXVVDRJESA-N
InChi Code	InChI=1S/C23H24N4O4/c1-27-19-12-17(7-8-20(19)31-23(27)29)16-5-3-15(4-6-16)11-18(13-24)26-22(28)21-14-25-9-2-10-30-21/h3-8,12,18,21,25H,2,9-11,14H2,1H3,(H,26,28)/t18-,21-/m0/s1
Chemical Name	(S)-N-((S)-1-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)ethyl)-1,4-oxazepane-2-carboxamide
Synonyms	Brensocatib; INS 1007;AZD7986;INS-1007;AZD-7986;INS1007; AZD 7986
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	Brensocatib (AZD7986), a dipeptidyl peptidase 1 (DPP1) inhibitor, has pIC50 values of 6.85, 7.6, 7.7, 7.8, and 7.8 in humans, mice, rats, dogs, and rabbits, respectively, according to the results of cell experiments. In propionaldehyde reactivity tests, brensocatib exhibits stability with a half-life of more than 50 hours. Following differentiation in the presence of 38 pM to 10 μM of Brensocatib, a concentration-dependent reduction in DPP1's and all three nsps' cytolytic enzyme activity—NE, Pr3, and CatG—was noted. With pIC50 values of roughly 7, brensocatib suppresses the activation of all three NSPs in a concentration-dependent manner. The level of activity has nearly entirely decreased. The activity of NE, Pr3, and CatG decrease to 4% to 10% of the control at 10 μM Brensocatib [1].
ln Vivo	Brensocatib (AZD7986) has a half-life of more than 10 hours and shows good stability in plasma. In vivo, brensocatib dose-dependently suppresses the activation of NE and Pr3, but not CatG, in lysates of bone marrow cells [1].
Animal Protocol	0.2, 2, and 20 mg/kg/day; oral Naive rats
References	[1]. Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986). J Med Chem. 2016 Oct 27;59(20):9457-9472.
Additional Infomation	Brensocatib is under investigation in clinical trial NCT03218917 (Assessment of INS1007 in Subjects With Non-cystic Fibrosis Bronchiectasis). Brensocatib is an orally bioavailable, small molecule, reversible inhibitor of dipeptidyl peptidase 1 (DPP1), with potential anti-inflammatory activity. Upon oral administration, brensocatib reversibly binds to and inhibits the activity of DPP1, thereby inhibiting the activation of neutrophil serine proteases (NSPs), including neutrophil elastase (NE), during neutrophil maturation. This inhibits the activity of NSPs, and may prevent lung inflammation and injury and improve lung function associated with NSPs-induced respiratory diseases. NSPs, serine proteases released by neutrophils during inflammation, is upregulated in a number of respiratory diseases. Drug Indication Treatment of non-cystic fibrosis bronchiectasis

Solubility Data

Solubility (In Vitro)

DMSO: >10 mM Water:N/A Ethanol:N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.95 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.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.3783 mL	11.8915 mL	23.7829 mL
	5 mM	0.4757 mL	2.3783 mL	4.7566 mL
	10 mM	0.2378 mL	1.1891 mL	2.3783 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.