Identification of 1-({[1-(4-Fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane Carboxylic Acid as a Selective Nonpeptide Neurotensin Receptor Type 2 Compound

Abstract

Compounds active at neurotensin receptors (NTS1 and NTS2) exert analgesic effects on different types of nociceptive modalities, including thermal, mechanical, and chemical stimuli. The NTS2 preferring peptide JMV-431 (2) and the NTS2 selective nonpeptide compound levocabastine (6) have been shown to be effective in relieving the pain associated with peripheral neuropathies. With the aim of identifying novel nonpeptide compounds selective for NTS2, we examined analogues of SR48692 (5a) using a FLIPR calcium assay in CHO cells stably expressing rat NTS2. This led to the discovery of the NTS2 selective nonpeptide compound 1-({[1-(4-fluorophenyl)-5-(2-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)cyclohexane carboxylic acid (NTRC-739, 7b) starting from the nonselective compound 5a.

Identification of N-[(5-{[(4-Methylphenyl)sulfonyl]amino}-3-(trifluoroacetyl)-1H-indol-1-yl)acetyl]-l-leucine (NTRC-824), a Neurotensin-like Nonpeptide Compound Selective for the Neurotensin Receptor Type 2

“…22 In this article, we report a parallel study that identified the NTS2 selective nonpeptide compound 5 that, like NT, is an antagonist of 3b in the FLIPR assay. The details of this work are presented herein.…”

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

“…We planned to follow up this assay with a binding assay using [ 125 I]NT to confirm interaction with NTS2. 29,30 Profiling compounds 3, 4, 5 and NT in our FLIPR assay revealed that 3 and 4 were full agonists whereas levocabastine ( 5 ) behaves as a potent partial agonist and NT was an antagonist of the calcium release mediated by 4 . This evidence guided our discovery efforts toward identification of compounds displaying either potent partial agonist or antagonist activity in the FLIPR assay.…”

“…The first of these was the NTS2 selective potent partial agonist 6 (NTRC-739) that was obtained from an SAR study starting with the nonselective full agonist 3 . 30 More recently, we identified an NT-like antagonist 7 starting from the screening of a library of substituted indole compounds based upon the NTS1 partial agonist 8. 31,32 In this article, we report the discovery of N -{[6-chloro-4-(2,6-dimethoxyphenyl)quinazolin-2-yl]carbonyl}-L-leucine (NTRC-808, 9 ) a novel nonpeptide chemotype that shows potent partial agonist activity in the FLIPR functional assay and is selective for NTS2 versus NTS1.…”

“…In addition to this, we planned to add 2,6-dimethoxy groups to the phenyl ring in 17 as these are known to be important to NT receptor recognition, calcium mobilization and selectivity. 30,38,39 Finally, we believed that replacement of the aminobenzoic acid in 17 for alpha amino acids known to be active at NT receptors would improve overall activity and receptor recognition. From previous experience, we chose the amino acids illustrated in Scheme 1 as the first set to be investigated.…”

“…From previous experience, we chose the amino acids illustrated in Scheme 1 as the first set to be investigated. 30,38,39 …”