Structure−Activity Relationship Study of First Selective Inhibitor of Excitatory Amino Acid Transporter Subtype 1: 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101)

Abstract

The excitatory amino acid transporters (EAATs) are expressed throughout the central nervous system, where they are responsible for the reuptake of the excitatory neurotransmitter (S)-glutamate (Glu). (1) Recently, we have reported the discovery of the first subtype selective EAAT1 inhibitor 2-amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) (1b) and presented an introductory structure-activity relationship (SAR) study. (2) Here, we present a detailed SAR by the design, synthesis, and pharmacological evaluation of analogues 1g-1t. By comparison of potencies of 1b, 1h, and 1i versus 1j, it is evident that potency is largely influenced by the chemical nature of the R(1) substituent. The study also demonstrates that any chemical change of the functional groups or a change to the parental scaffold results in the complete loss of inhibitory activity of the compounds at EAAT1. Finally, a bioavailability study of UCPH-101 determined the half-life to be 30 min in serum (rats) but also that it was not able to penetrate the blood-brain barrier to any significant degree.

Structure–Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree–Fock Calculations

“…The synthesis of the UCPH-101/ 102 compound class ( Figure 1) is in general terms carried out by a three-component reaction (Figure 2). 13 The R 1 substituent in the 7-position of the parental skeleton C originates from diketone A, whereas the R 2 substituent is derived from aldehyde B.…”

“…3,13 On the other hand, the 4-position (R 2 ) was found to be able to accommodate substituents of various sizes, not being restricted to aromatic moieties (compounds 1−3, Figure 1). Furthermore, two methyl groups or no substituent in the 4-position was observed to result in complete loss of inhibitory activity at EAAT1 (compounds 4− 5, Figure 1).…”

“…Unfortunately, lactam 6 and lactone 7 were both without inhibitory activity at EAAT1. 13 To continue the objective, the strategy was modified as to introduce a nitrogen atom in the 7-position ( Figure 4). By this tactic, the four stereoisomers is reduced to two, although it is unclear what the consequence of the presence of a basic nitrogen is for EAAT1 inhibitory activity (Figure 4).…”

“…11,12 We have recently reported the first class of selective EAAT1 inhibitors and a first structure−activity-relationship (SAR) study. 13,14 The analogues UCPH-101 and UCPH-102 were the most potent inhibitors in the series (IC 50 values 0.66 and 0.43 μM, respectively) ( Figure 1). 13,14 Comprising two chiral centers, all analogues in the series were synthesized and characterized pharmacologically as a mixture of four stereoisomers ( Figure 2), however, the inhibitory activity resides in only two of these.…”

“…13,14 Comprising two chiral centers, all analogues in the series were synthesized and characterized pharmacologically as a mixture of four stereoisomers ( Figure 2), however, the inhibitory activity resides in only two of these. 13 In this paper, we present the elucidation of the stereochemical configuration in correlation with inhibitory activity for this new class of selective EAAT1 inhibitors.…”