Insertion of an Aspartic Acid Moiety into Cyclic Pseudopeptides:  Synthesis and Biological Characterization of Potent Antagonists for the Human Tachykinin NK-2 Receptor

Abstract

A new series of monocyclic pseudopeptide tachykinin NK-2 receptor antagonists has been derived from the lead compound MEN11558. A synthesis for these molecules sharing the same intermediate was designed and performed. The replacement of the succinic moiety with an aspartic acid and the functionalization of its amino group with a wide variety of substituents led to very potent and selective NK-2 antagonists. Best results were obtained through the insertion in position 12 of an amino group with R configuration, linked by a short spacer to a saturated nitrogen heterocycle (morpholine, piperidine, or piperazine). The study led to compounds 54 and 57, endowed with high in vivo potency at very low doses and long duration of action in animal models of bronchoconstriction. In particular 54 and 57 completely inhibited NK-2 agonist induced bronchoconstriction in guinea pig after intratracheal administration at subnanomolar doses (ED(50) = 0.27 nmol/kg and 0.15 nmol/kg, respectively).

Morpholine as a privileged structure: A review on the medicinal chemistry and pharmacological activity of morpholine containing bioactive molecules

“…A peptidomimetic approach towards a potent and selective NK 2 antagonist for the treatment of respiratory diseases by Menarini Ricerche yielded the cyclohexapeptide 90 (Figure ) . This molecule was developed based on the initial lead MEN‐11558 ( 91 ) by variable substitution at position 12, of which the morpholine containing derivative was selected.…”

Structure−Activity Relationships of 6-Methyl-benzo[b]thiophene-2-carboxylic Acid (1-{(S)-1-Benzyl-4-[4-(tetrahydropyran-4-ylmethyl)piperazin-1-yl]butylcarbamoyl}cyclopentyl)amide, Potent Antagonist of the Neurokinin-2 Receptor

“…All experiments were performed in oxygenated (96% O 2 and 4% CO 2 ) Krebs−Henseleit solution. The preparations were set up according to methods previously described . The activity of test compounds at tachykinin NK 2 receptors in GPC was assessed against selective NK 2 receptor agonist [βAla 8 ]-NKA(4−10) in the presence of the NK 1 receptor selective antagonist SR 140333 (1 μM).…”

Synthesis and Conformational Analysis of Cyclotetrapeptide Mimetic β‐Turn Templates and Validation as 3D Scaffolds

“…The cyclic tetrapeptide analogues were prepared by solid‐phase coupling of two dipeptide analogues 6 and 7 . Fragment 6 was prepared by a standard solution‐phase procedure by coupling Fmoc‐Phe‐OH and Boc‐protected diamine 5 ,10b, 11 obtained, in turn, by reduction of Boc‐PheNH 2 with BH 3 12. The dipeptide was deprotected with dimethylamine (DMA), and the resulting crude product 6 was used without purification.…”

“…HOBt (0.12 g, 0.9 mmol) was added to a stirred solution of Fmoc‐Phe‐OH (0.29 g, 0.75 mmol) in 9/1 CH 2 Cl 2 /DMF (9:1, 10 mL) at room temperature. After 10 min, 5 10b, 11 (0.19 g, 0.75 mmol, 94 % pure by chiral HPLC analysis, see General methods ), EDCI⋅HCl salt (0.19 g, 0.9 mmol) and TEA (0.15 mL, 1.1 mmol) were added while stirring at room temperature. After 3 h, the mixture was diluted with CH 2 Cl 2 , and the solution was washed with 0.5 M HCl, and saturated Na 2 CO 3 .…”