Novel Small Molecule Adjuvants to Drug-eluting Stents

DESCRIPTION (provided by applicant): Currently approved drug-eluting stents are plagued by late-stage thrombosis and delayed restenosis. Acceleration of stent re-endothelialization can suppress neointimal hyperplasia, promote healing of the vessel wall, an d decrease restenosis rates. Scatter factor/hepatocyte growth factor (SF/HGF) promotes endothelial cell proliferation and migration. Feasibility of using an SF/HGF coat as an adjuvant on drug-eluting stents is compounded by issues relating to gene and prot ein therapy. Angion Biomedica is pursuing the development of small molecules that regulate SF/HGF/c-Met signaling to therapeutic advantage. Based on the 3-dimensional structure of the ATP-binding site of the SF/HGF receptor c-Met's tyrosine kinase domain a nd using a product discovery engine comprising phage display, 3-dimensional molecular modeling, protein chemistry and preclinical biology, we have identified a phthalazin-1 (2H)-one scaffold with potential SF/HGF-like bioactivity. Rational drug design-driv en side-chain additions onto this scaffold led to the identification of Ang 1170, the first small molecule drug-like member within this class. Preliminary data indicate that Ang 1170 activates the SF/HGF/c-Met pathway, stimulates endothelial cell prolifera tion, and protects against endothelial cell death. Importantly, Ang 1170 has no effects on fibroblast or vascular smooth muscle cell proliferation. We have since constructed a structural library around the phthalazin-1 (2H)-one scaffold comprising 21 compo unds with potential SF/HGF-like bioactivity, the eventual goal being the identification of an SF/HGF-like small molecule that is not only bioeffiacious and potent but also carries a safety profile compatible with human use. The goal of this Phase I applica tion is to couple targeted proteomics and medicinal chemistry to an in vivo bioefficacy assay in order to identify lead and fallback candidates within this phthalazin-1 (2H)-one library for stimulation of the endothelial cell proliferation program. The two candidates emerging from this Phase I program will then be submitted to in-depth, preclinical SBIR Phase II studies comprising in vivo models of in-stent restenosis, biodistribution studies, and formal regulatory/safety studies. The ultimate goal of this study is to advance an SF/HGF-like small molecule to the clinic for use as an adjuvant coat on currently used drug-eluting stents.Late stage thrombosis and delayed restenosis plague currently approved drug-eluting stents and remains a significant cause of morbidity and mortality. A small molecule therapeutic that reduces restenosis has tremendous clinical benefit.