8DEA

Scaffold Hopping via Ring Opening Enables Identification of Acyclic Compounds as New Complement Factor D Inhibitors

Summary for 8DEA

• Entry DOI: 10.2210/pdb8dea/pdb
• Related: 1BFP 1DIC
• Descriptor: Complement factor D, 1-[(3-acetylphenyl)acetyl]-N-(6-bromopyridin-2-yl)-L-prolinamide, GLYCEROL, ... (4 entities in total)
• Functional Keywords: serine protease inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 100293.23

Authors

Raman, K.,Babu, Y.S. (deposition date: 2022-06-20, release date: 2022-11-02, Last modification date: 2024-10-23)

Primary citation

Zhang, W.,Wu, M.,Vadlakonda, S.,Juarez, L.,Cheng, X.,Muppa, S.,Chintareddy, V.,Vogeti, L.,Kellogg-Yelder, D.,Williams, J.,Polach, K.,Chen, X.,Raman, K.,Babu, Y.S.,Kotian, P.
Scaffold hopping via ring opening enables identification of acyclic compounds as new complement Factor D inhibitors.
Bioorg.Med.Chem., 74:117034-117034, 2022

PubMed Abstract: The three complement pathways comprising the early phase of the complement system (the classical, lectin, and alternative pathways) act together with the innate and adaptive immune systems to protect against foreign entities and maintain tissue homeostasis. While these systems are normally under tight regulatory control, several diseases have been reported to correlate with uncontrolled activation and amplification of the alternative pathway, including paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, C3 glomerulopathy, and age-related macular degeneration. Complement FactorD (CFD), a serine protease, is the rate-limiting enzyme for the activity of alternative pathway. CFD activates the alternative pathway by cleaving Complement Factor B complexed to C3b (C3bB) to generate alternative pathway C3 convertase (C3bBb). In our search for novel CFD inhibitors with therapeutic potential, we employed a hot-spot analysis of an ensemble of apo and holo CFD structures. This analysis identified potential pharmacophore features that aided in the design of a series of compounds based on an l-proline core. While these compounds inhibited CFD in an esterolytic assay (for example, a proline-based compound, IC = 161 nM), the pharmacokinetic (PK) properties were poor. A strategy of scaffold hopping via ring opening led to a novel series of acyclic compounds, with subsequent structure-based ligand design and lead optimization producing several novel CFD inhibitors. One of these inhibitors, 1-(2-((2-(3-chloro-2-fluorobenzylamino)-2-oxoethyl)(cyclopropyl)amino)-2-oxoethyl)-5-(3-methyl-3-(1-methylpiperidin-4-yl)ureido)-1H-indazole-3-carboxamide, showed good potency with ICs of 37 nM in the esterolytic assay and 30 nM in a hemolytic assay and PK assessments following oral administration to rats revealed a C of 113 ng/mL and an AUC of 257 hr.ng/mL.

PubMed: 36272185
DOI: 10.1016/j.bmc.2022.117034

Experimental method

X-RAY DIFFRACTION (2.214 Å)