Synthesis, Structure–Activity Relationships and Brain Uptake of a Novel Series of Benzopyran Inhibitors of Insulin-Regulated Aminopeptidase

Abstract

Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) enhance fear avoidance and spatial memory and accelerate spatial learning in a number of memory paradigms. Using a virtual screening approach, a series of benzopyran compounds was identified that inhibited the catalytic activity of IRAP, ultimately resulting in the identification of potent and specific inhibitors. The present study describes the medicinal chemistry campaign that led to the development of the lead candidate, 3, highlighting the key structural features considered as critical for binding. Furthermore, the in vivo pharmacokinetics and brain uptake of compounds (1 and 3) were assessed in rats and were complemented with in vitro human and rat microsomal stability studies. Following intravenous administration to rodents, 3 exhibits brain exposure, albeit it is rapidly converted to 1, a compound which also exhibits potent inhibition of IRAP.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…With a bioinformatics in silico screening approach, a large library of compounds against a structure homology of IRAP Albiston et al, 2011) benzopyran compounds were identified, synthesized, and optimized; the highest affinity compound HFI-437 has a pK i of 7.70 for IRAP. The latter nonpeptide inhibitors were found to enhance the performance of rats in different memory paradigms (Mountford et al, 2014). Yang et al (2008) used IRAP/AngIV binding siteselective ligands, LVV-hemorphin-7 and AT4-16, for intravenous, intrarenal, and intracerebroventricular infusion to discriminate AngIV effects through AT 1 and AngIV binding sites.…”

Binding to and Inhibition of Insulin-Regulated Aminopeptidase by Macrocyclic Disulfides Enhances Spine Density

“…Both potent and specific drug-like IRAP inhibitors (Borhade et al, 2014;Mountford et al, 2014), some with proven effects in vivo (Albiston et al, , 2011, and inhibitors with more peptidic character (Kobori et al, , 1998Wolfe, 2002;Axen et al, 2006;Axen et al, 2007;Andersson et al, 2008;Lukaszuk et al, 2008Lukaszuk et al, , 2009Hallberg, 2009) have been disclosed by us and others. We use an approach to discover efficient Ang IV peptidomimetics that relies on stepwise alterations of Ang IV by applying various cyclization procedures to restrict conformational flexibility and to allow determination of the bioactive conformation of Ang IV when it binds to IRAP (Axen et al, 2006(Axen et al, , 2007.…”

Efficient tandem synthesis of a variety of pyran-annulated heterocycles, 3,4-disubstituted isoxazol-5(4H)-ones, and α,β-unsaturated nitriles catalyzed by potassium hydrogen phthalate in water

“…HA14-1 (F) is an antagonist for antiapoptotic Bcl-2 proteins which can effectively induce apoptosis of human acute myeloid leukemia cells [37]. Compounds G and H have a benzopyran core and are non-peptidic insulin-regulated aminopeptidases (IRAP) that can enhance memory in two memory models [38] [39]. Taking into consideration these characteristics of derivatives of highly functionalized 4H-chromenes and 4H-pyrans, much attention has been focused on the development of ecologically benign methods for synthesis of such useful heterocyclic structures by multicomponent cyclization of a variety of aldehydes, C-H enolizable molecules, and methylene-containing compounds.…”