Identification of N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (NTRC-808), a novel nonpeptide chemotype selective for the neurotensin receptor type 2

Abstract

Compounds acting via the GPCR neurotensin receptor type 2 (NTS2) display analgesic effects in relevant animal models. Using a pharmacophore model based on known NT receptor nonpeptide compounds, we screened commercial databases to identify compounds that might possess activity at NTS2 receptor sites. Modification of our screening hit to include structural features known to be recognized by NTS1 and NTS2, led to the identification of the novel NTS2 selective nonpeptide, N-{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-l-leucine (9). This compound is a potent partial agonist in the FLIPR assay with a profile of activity similar to that of the reference NTS2 analgesic nonpeptide levocabastine (5).

Keywords: FLIPR assay; Levocabastine; NTS2 receptor; Neurotensin; Pain; SR142948a; SR48692.

Figure 1

3D-Pharmacophore derived from compounds 3, 4, 5, and 6.

Figure 2

Compound 9 shows potent partial agonist activity versus the agonist standard compound 4 in the rNTS2 FLIPR assay.

Chart 1

Structures of neurotensin reference peptides (1, 2), reference nonpeptides (3-5), and recently described NTS2 selective nonpeptide compounds (6,7) and title compound (9).

Chart 2

Targeted modifications of latent hit 17 to improve activity at NT receptors

Scheme 1

Synthetic route to target compounds 9, 14b and 16b. Reagents and conditions: (i) Ac₂O, Et₂O, reflux; (ii) veratrole, n-BuLi, 0°C; HCl, EtOH, H₂O; (iii) aqueous glyoxalic acid, NH₄OAc; (iv) DMF, RT, air, 3 days; (v) HBTU, Et₃N, CH₂Cl₂, L-cyclohexylglycine tert-butyl ester•HCl; (vi) HBTU, Et₃N, CH₂Cl₂, L-leucine tert-butyl ester•HCl; (vii) HBTU, Et₃N, CH₂Cl₂, 1-aminocyclohexylcarboxylic acid methyl ester•HCl; (viii) TFA, CH₂Cl₂; (ix) LiOH, dioxane.