Products - DPPI inhibitors

The search for DPPI inhibitors with optimal properties has been based on screening libraries of potential small molecule inhibitors with dipeptide scaffold structures that could fulfil the criteria that is defined for an oral available DPPI inhibitor drug candidate.

The initial screening had a focus on identifying potent and cell-permeable compounds with high selectivity versus other proteases, which historically has been a major challenge in developing DPPI inhibitors. Out of about 900 compounds a small number was further characterized with respect to metabolic stability and in vitro toxicology.

The DPPI crystal structure elucidation and co-crystallization with DPPI inhibitors has been performed in order to understand the structure activity relationship (SAR).

Status

The Neuprozyme lead compound XPZ-50 has a clean pharmacological profile, including in vitro toxicology. 

XPZ-50 is a stable compound that has been formulated for oral dosing in humans.

Dose dependent effect on NE, CatG and PR3 activities in bone marrow and circulating neutrophils has been demonstated in animal models. 

XPZ-50 is ready for preclinical safety assessment before entering into a Phase I first-in-human and proof-of-mechanism study in healthy volunteers induced with a mild inflammation.

This will establish XPZ-50 as a clinical drug candidate with potential to significantly improve patients' lives in a number of pulmonary diseases that involve neutrophil mediated inflammation.  

Selected literature

 

Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases.
Guarino C, Hamona Y, Croix C, Lamort A-S, Dallet-Choisy S, Marchand-Adama S, Lesner A, Baranek T, Viaud-Massuard M-C, C, Lauritzen C, Pedersen J, Heuz.-Vourc'h N, Si-Tahar M, Erhan Fıratlı E, Jenne DE, Gauthier F, Horwitz MS, Borregaard N, and Korkmaz B. Biochem Pharmacol. 2017 May 1;131:52-67. 

Elastase activity on sputum neutrophils correlates with severity of lung disease in cystic fibrosis. 
Dittrich AS, Kühbandner I, Gehrig S, Rickert-Zacharias V, Twigg M, Wege S, Taggart CC, Herth F, Schultz C, Mall MA. Eur Respir J. 2018 Mar 29;51(3). 

Lack of Neutrophil Elastase Reduces Inflammation, Mucus Hypersecretion, and Emphysema, but Not Mucus Obstruction, in Mice with Cystic Fibrosis–like Lung Disease. 
Gehrig, Duerr J, Weitnauer M, Wagner CJ, Graeber SY, Schatterny J, Hirtz S, Belaaouaj A, Dalpke AH, Schultz C, Mall MA. Am J Respir Crit Care Med. 2014;189:1082-92. 

Early lung disease in cystic fibrosis. 
Grasemann H, Ratjen F. Lancet Respir Med 2013;1:148–157. 

Lung disease at diagnosis in infants with cystic fibrosis detected by newborn screening. 
Sly PD, Brennan S, Gangell C, de Klerk N, Murray C, Mott L, Stick SM, Robinson PJ, Robertson CF, Ranganathan SC; Australian Respiratory Early Surveillance Team for Cystic Fibrosis (AREST-CF). Am J Respir Crit Care Med 2009;180:146–152. 

Risk factors for bronchiectasis in children with cystic fibrosis. 
Sly PD, Gangell CL, Chen L, Ware RS, Ranganathan S, Mott LS, Murray CP and Stick SM. The New England journal of medicine 2013; 368 (21): 1963 – 70.

Therapeutic targeting of cathepsin C: from pathophysiology to treatment. 
Korkmaz B, Caughey GH, Chapple I, Gauthier F, Hirschfeld J, Jenne DE, Kettritz R, Lalmanach G, Lamort AS, Lauritzen C, Łȩgowska M, Lesner A, Marchand-Adam S, McKaig SJ, Moss C, Pedersen J, Roberts H, Schreiber A, Seren S, Thakker NS. Pharmacol Ther. 2018 May 26. pii: S0163-7258(18)30091-3.