PRCP INHIBITOR (C15-1304-227)

General description

A dichlorobenzimidazolopyrrolidinamide compound that acts as a highly potent PrCP-selective inhibitor (IC₅₀ = 1 nM against human PrCP; IC₅₀ = 2 and 8 nM against mouse PrCP, respectively, in the absence or presence of 1% mouse serum albumin), presumably via non-covalent catalytic site interaction, while exhibiting no significant potency toward panels of ion channels, receptors, and enzymes, including homologous serine proteases QPP, FAP, PEP, ACE2, DPP4, DPP8, and DPP9 (IC₅₀ >25 µM). Oral administration (100 mg/kg/d for 5 d) is reported to result in significant food intake reduction and body fat loss among high fat diet-induced obese mice in vivo.

A dichlorobenzimidazolopyrrolidinamide compound that acts as a highly potent PrCP-selective inhibitor (IC₅₀ in the absence/presence of 1% mouse serum albumin = 1 nM/1 nM and 2 nM/8 nM, respectively, against human and mouse PrCP-catalyzed Mca-APK(Dnp)-OH hydrolysis; Initial [Substrate] = 25 µM), presumably via non-covalent catalytic site interaction, while exhibiting no significant potency toward panels of ion channels, receptors, and enzymes, including homologous serine proteases QPP, FAP, PEP, ACE2, DPP4, DPP8, and DPP9 (IC₅₀ >25 µM). Despite its being a substrate of P-gp efflux transporters and ineffective CNS delivery across blood-brain barrier, peripheral PrCP inhibition via oral administration (100 mg/kg/d for 5 d; [Drug] = 380 nM and 50 nM, respectively, in blood and brain 24 h after last p.o. dosing) is reported to result in significant food intake reduction and body fat loss among high fat diet-induced obese mice (0.73 g fat reduction vs. 0,73 g fat gain in 5 d, respectively, with drug or vehicle treatment) in vivo. Drug treatment among PrCP^-/- obsese mice in comparison, results in only 1.1% weight loss primarily due to a decreased gain in muscle mass and little change in body fat.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
PrCP

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

Use only fresh DMSO for reconstitution.

Other Notes

Wu, Z., et al. 2012. Bioorg. Med. Chem. Lett.22, 1774.
Graham, T.H., et al. 2012. Bioorg. Med. Chem. Lett.22, 658.
Zhou, C., et al. 2010. J. Med. Chem.53, 7251.

Legal Information

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Molecular Weight: 578.53. Empirical Formula: C₃₁H₃₃Cl₂N₅O₂. Assay: ≥. 97% (HPLC). Quality Level: 100. form: powder. manufacturer/tradename: Calbiochem^®. . storage condition: OK to freeze. color: white. solubility: DMSO: 100 . mg/mL. storage temp.: −. 20°C. Storage Class Code: 11 - Combustible Solids. WGK: WGK 3. Flash Point(F): Not applicable. Flash Point(C): Not applicable.