Novel potent and selective alphavbeta3/alphavbeta5 integrin dual antagonists with reduced binding affinity for human serum albumin.

The binding of lead compounds and drugs to human serum albumin (HSA) is a ubiquitous problem in drug discovery since it modulates the availability of the leads and drugs to their intended target, which is linked to biological efficacy. In our continuing efforts to identify small molecule αVβ3 and αVβ5 dual antagonists, we recently reported indoles 2–4 as potent and selective αVβ3/αVβ5 antagonists with good oral bioavailability profile. In spite of subnanomolar binding affinity of these compounds to human αVβ3 and αVβ5 integrins, high HSA binding (96.5–97.3%) emerged as a limiting feature for these leads. Structure–activity HSA binding data of organic acids reported in the literature have demonstrated that the incorporation of polar groups into a given molecule can dramatically decrease the affinity toward HSA. We sought to apply this strategy by examining the effects of such modifications in both the central core constrain and the substituent β to the carboxylate. Most of these derivatives were prepared in good yields through a cesium fluoride-catalyzed coupling reaction. This reaction was successful with a variety of nitrogen-containing scaffolds (20, 33, and 43) and selected acetylenic derivatives (16, 19, and 34). Among the compounds synthesized, the 3-[5-[2-(5,6,7,8-tetrahydro [1,8]naphthyridin-2-yl)ethoxy]indol-1-yl]-3-[5-(N,N-dimethylaminomethyl)-3-pyridyl]propionic acid (25) was found to be the most promising derivative within this novel series with a subnanomolar affinity for both αvβ3 and αvβ5 (IC50=0.29 and 0.16 nM, respectively), similar to our initial lead receptor antagonists 2–4, and exhibiting a low HSA protein binding (40% bound, Kd=1.1±0.4 × 103 μM) and an improved in vitro stability profile toward human and mouse microsomes (99.9% and 98.7% remaining after 10 min). Moreover, the selectivity of 25 toward α5β1 and IIbIIIa integrins was perfectly maintained when compared to the parent leads 2–4. Thus, compound 25 was selected as a new lead with improved drug-like properties for further evaluations in the field of oncology and osteoporosis.