Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4β1 and α4β7 receptor antagonists

Synthesis and Biological Evaluation of Cyclobutane-Based β3 Integrin Antagonists: A Novel Approach to Targeting Integrins for Cancer Therapy

“…We rationalised that the methyl esters would be rapidly hydrolysed by esterases in cells and in vivo to yield the acid group required for binding to the β3 MIDAS [ 72 , 73 ], and the presence of methyl ester would improve the lipid solubility and PK properties of the compounds [ 83 , 84 , 85 ]. The free acids required to test the compounds in cell-free assays were obtained from selected RGD-mimetic esters by a treatment with aqueous HCl ( Scheme 3 ).…”

Functionalized Organozinc Reagents in Medicinal Chemistry: Discovery of Novel Drug Candidates

“…The initial reaction between the pyridone iodide 9 (R 1 = Me, R 2 = H) with activated zinc dust resulted in the formation of the corresponding zinc intermediate which underwent a smooth coupling reaction with 4-iodo-L-phenylalanine 10 in the presence of Pd(dba) 2 and tri-o-tolylphosphine to afford the desired product 11 in 34% yield (Scheme 3). 22 Moreover, this reaction was very general and was readily extended to the electron-deficient 4-and 6-trifluoromethyl-substituted pyridones to afford the corresponding coupling products, 12 and 13 in moderate yield. These were then converted into the target compounds 14a-c in three steps (Scheme 3).…”

“…A prodrug relative to 14 (R 1 = CF 3 , R 2 = Me) was selected for early development for the treatment of inflammatory bowel diseases, which are partially driven by high expression of alpha4 beta7 integrin in intestinal epithelium. 22 In complementary studies, we investigated the synthesis of a related pyrimidinedione series and thanks to our experience with the pyridones, utilized organozinc chemistry for the key coupling step from the outset. Accordingly, each of the iodides 15 reacted smoothly with activated zinc dust at 70 °C over the course of a few hours and the resulting organozinc intermediates were allowed to react with 4-iodo-L-phenylalanine 10 at 55 °C in the presence of Pd(dba) 2 and tri-2-furylphosphine.…”

Novel Ligands Targeting α4β1 Integrin: Therapeutic Applications and Perspectives

“…Linking these molecules at each of the termini of a three-arm branched PEG provided potent in vivo α 4 integrin inhibitors (Smith et al, 2013). In general, due to the high similarity of the α 4 β 1 and α 4 β 7 integrins receptors, several cases of dual ligands have been reported in the literature (Tilley et al, 2013). Finally, among the phenylalanine containing dipeptides, particular interest has been recently paid to GW559090, for its effects on corneal staining and ocular surface inflammation in murine model of DED (Krauss et al, 2015).…”