Structure Activity Relationships of α_v Integrin Antagonists for Pulmonary Fibrosis by Variation in Aryl Substituents

Abstract

Antagonism of αvβ6 is emerging as a potential treatment of idiopathic pulmonary fibrosis based on strong target validation. Starting from an αvβ3 antagonist lead and through simple variation in the nature and position of the aryl substituent, the discovery of compounds with improved αvβ6 activity is described. The compounds also have physicochemical properties commensurate with oral bioavailability and are high quality starting points for a drug discovery program. Compounds 33S and 43E1 are pan αv antagonists having ca. 100 nM potency against αvβ3, αvβ5, αvβ6, and αvβ8 in cell adhesion assays. Detailed structure activity relationships with these integrins are described which also reveal substituents providing partial selectivity (defined as at least a 0.7 log difference in pIC50 values between the integrins in question) for αvβ3 and αvβ5.

Relative Binding Affinities of Integrin Antagonists by Equilibrium Dialysis and Liquid Chromatography–Mass Spectrometry

“…Compound 2 is an established integrin antagonist from Merck KGaA, 8 while 3 is a Nottingham-GSK compound. 7 The results, summarized in Table 1, showed a good correlation between the ED-determined f b values and the pIC 50 values of the three compounds. Inhibitors 50 , gave the highest f b .…”

“…The ability of this series of compounds to inhibit α v β 6 activity was demonstrated by a cell adhesion assay. 7 Although able directly and reliably to detect inhibition of the α v β 6 -LAP interaction, the assay requires access to, and maintenance of, a transfected human cell line overexpressing α v β 6 . We therefore wished to construct a simple, rapid, and sensitive competitive assay to rank the order of α v β 6 target binding, and chose to examine the suitability of equilibrium dialysis (ED), with LC-MS detection, for this purpose.…”

“…Structure−activity relationships for compounds 3−9 are described elsewhere. 7 Triazole spacers between Arg and Asp mimetics having micromolar inhibitory activity for α v β 3 and a v β 5 are precedented, 21 but introduction of a triazole spacer in this series as in 10 causes at least a 10-fold drop in activity against α v β 6 (cf. 7).…”

Late‐Stage Functionalization by Chan–Lam Amination: Rapid Access to Potent and Selective Integrin Inhibitors

“…Previous work in our group led to the development of a pan‐integrin inhibitor, the 3‐CF 3 ‐substituted β‐aryl‐β‐amino acid derivative 4 , pan in this case referring to the fact that compound 4 exhibits broadly similar levels of potency towards multiple integrins . Whilst compound ( S )‐ 4 displayed appropriate physiochemical properties (ChromLogD 2.73, permeability >100 nm s −1 , aqueous solubility >300 μ m ) and was therefore considered as lead‐like, comparison with GSK3008348 3 , and other analogues, revealed significant differences in potency and selectivity (Figure ).…”

“…The structures are coloured to show how 3 and 4 mimic the basic and acidic sites in the RGD sequence. Selectivity and potency data from cell adhesion assays are shown …”