Discovery of (S)-3-(3-(3,5-Dimethyl-1H-pyrazol-1-yl)phenyl)-4-((R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic Acid, a Nonpeptidic α_vβ₆ Integrin Inhibitor for the Inhaled Treatment of Idiopathic Pulmonary Fibrosis

Abstract

A series of 3-aryl(pyrrolidin-1-yl)butanoic acids were synthesized using a diastereoselective route, via a rhodium catalyzed asymmetric 1,4-addition of arylboronic acids in the presence of ( R)-BINAP to a crotonate ester to provide the ( S) absolute configuration for the major product. A variety of aryl substituents including morpholine, pyrazole, triazole, imidazole, and cyclic ether were screened in cell adhesion assays for affinity against αβ, αβ, αβ, αβ, and αβ integrins. Numerous analogs with high affinity and selectivity for the αβ integrin were identified. The analog ( S)-3-(3-(3,5-dimethyl-1 H-pyrazol-1-yl)phenyl)-4-(( R)-3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)pyrrolidin-1-yl)butanoic acid hydrochloride salt was found to have very high affinity for αβ integrin in a radioligand binding assay (p K = 11), a long dissociation half-life (7 h), very high solubility in saline at pH 7 (>71 mg/mL), and pharmacokinetic properties commensurate with inhaled dosing by nebulization. It was selected for further clinical investigation as a potential therapeutic agent for the treatment of idiopathic pulmonary fibrosis.

13C CPMAS NMR as a Tool for Full Structural Description of 2-Phenyl Substituted Imidazoles That Overcomes the Effects of Fast Tautomerization

“…In all cases, at least two signals were missing in these spectra even if highly extended transient numbers were used (with number of scans of 1024 or 2048, Figures S29 and S39 for 2b and 2c , respectively). These observations are partly in accordance with earlier reported data on 2-phenyl imidazoles where either no or incomplete 13 C-NMR assignments are provided [ 16 , 17 ]. This incompleteness could be explained with the time scale of tautomeric exchange in solutions, which might be comparable with that of the 13 C-NMR experiment.…”

“…The carbon atoms in direct proximity to the tautomerizing sites of the molecule are most affected and their signals are usually not observed in conventional 13 C-NMR spectra. Therefore, the presentation of 13 C-NMR spectra of a given compound is sometimes omitted in literature [ 16 , 17 ]. In other cases, aiming at higher precision, significantly longer time for acquisition has been sacrificed to make the missing signals appear acceptably well, as can be seen in the Supplementary Materials of some papers [ 18 , 19 ].…”

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

“…During development of GSK3008348, characterization of the pharmacology, the physico-chemical, and PK properties of the molecule were assessed to track suitability for inhaled delivery. Most of these properties were evident in the GSK3008348 molecule except for lung retention 27 . Therefore, the duration of action of this inhaled molecule was designed to be driven by the PD of the interaction between GSK3008348 and the αvβ6 integrin.…”

A positron emission tomography imaging study to confirm target engagement in the lungs of patients with idiopathic pulmonary fibrosis following a single dose of a novel inhaled αvβ6 integrin inhibitor

“…The expression of αvβ6 is upregulated in IPF lung tissue [4], and increased levels of αvβ6 are associated with disease progression and poor prognosis [5], suggesting that an inhibitor of αvβ6 may provide therapeutic benefits to patients with IPF. GSK3008348 is a novel, small molecule αvβ6 integrin inhibitor that has been developed for inhaled delivery via nebulisation and is the first inhaled compound in this class [6]. In vitro, GSK3008348 demonstrates selective and high affinity binding to the αvβ6 integrin, inducing fast internalisation and degradation of the integrin.…”