1,4-Benzodiazepin-2-one derived neurokinin-1 receptor antagonists

Armour, Duncan; Aston, N.M.; Morriss, Karen M. L.; Congreve, Miles; Hawcock, A.B.; Marquess, Daniel G.; Mordaunt, Jackie E.; Richards, Stephen A.; Ward, P.

doi:10.1016/s0960-894x(97)00353-3

Cited by 13 publications

(5 citation statements)

References 17 publications

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“…These compounds were structurally analogous to investigated benzodiazepines of type 4 (Figure 1) that possessed the desired NK1R antagonism. 14 In this benzodiazepine series, as described by Armour et al, the role and necessity of the third aromatic moiety were questioned, and this motivated us to make the compounds without the 1-phenyl substitution (Scheme 2). As mentioned in the Introduction, numerous examples of NK1R antagonists containing only two aromatics are published (selected examples: 1-3 and 5 in Figure 1).…”

Section: ' Results and Discussionmentioning

confidence: 99%

“…These compounds were structurally analogous to investigated benzodiazepines of type 4 (Figure ) that possessed the desired NK1R antagonism . In this benzodiazepine series, as described by Armour et al, the role and necessity of the third aromatic moiety were questioned, and this motivated us to make the compounds without the 1-phenyl substitution (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…The 1-phenyl-benzazepine core 9 (R 1 = Ph) was chosen as an alternative for the benzodiazepine core in 4 (Figure 1), 14 whereas the indoloazepine core 10 could be considered to lead to a constrained analogue of the potent antagonist 5 . 15 …”

Section: Introductionmentioning

confidence: 99%

“…32,33 In this work, we present the 3 0 ,5 0 -bistrifluoromethyl benzyl derivatization of the conformationally constrained amino acids Aba 9 and Aia 10 and, in addition, of the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) 11 and Tcc 12 templates for the development of new NK1R antagonists. The 1-phenylbenzazepine core 9 (R 1 = Ph) was chosen as an alternative for the benzodiazepine core in 4 (Figure 1), 14 whereas the indoloazepine core 10 could be considered to lead to a constrained analogue of the potent antagonist 5. 15 The biological evaluation of all newly prepared compounds for NK1R antagonism led to the identification of three potent antagonists.…”

Section: ' Introductionmentioning

confidence: 99%

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Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

et al. 2011

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A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3′,5′-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn] and 23 [Ac-Tic-NMe-3′,5′-(CF3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R. The most active NK1 antagonist of the series, 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], was then used in the design of a novel, potent chimeric opioid agonist-NK1 receptor antagonist, 35 [Dmt-D-Arg-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], which combines the N-terminus of the established Dmt1-DALDA agonist opioid pharmacophore (H-Dmt-D-Arg-Phe-Lys-NH2) and 20, the NK1R ligand. The opioid component of the chimeric compound 35, i.e. Dmt-D-Arg-Aba-Gly-NH2 36, also proved to be an extremely potent and balanced μ- and δ opioid receptor agonist with subnanomolar binding and in vitro functional activity.

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Section: ' Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: ' Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist

et al. 2011

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“…The latter result indicated that in these constrained peptidomimetics, an indole ring is not essential for NK-1 affinity and can be replaced by a benzene ring, as had already been demonstrated in a variety of non-peptide NK-1 antagonists . Additionally, the benzodiazepinone antagonist 129 served as an inspiration to design the 1-phenyl-substituted Aba analogue 130 , which unfortunately turned out to be inactive (Figure ).…”

Section: Neurokinin-1mentioning

confidence: 99%

Side Chain Cyclized Aromatic Amino Acids: Great Tools as Local Constraints in Peptide and Peptidomimetic Design

et al. 2016

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Constraining the conformation of flexible peptides is a proven strategy to increase potency, selectivity, and metabolic stability. The focus has mostly been on constraining the backbone dihedral angles; however, the correct orientation of the amino acid side chains (χ-space) that constitute the peptide pharmacophore is equally important. Control of χ-space utilizes conformationally constrained amino acids that favor, disfavor, or exclude the gauche (-), the gauche (+), or the trans conformation. In this review we focus on cyclic aromatic amino acids in which the side chain is connected to the peptide backbone to provide control of χ- and χ-space. The manifold applications for cyclized analogues of the aromatic amino acids Phe, Tyr, Trp, and His within peptide medicinal chemistry are showcased herein with examples of enzyme inhibitors and ligands for G protein-coupled receptors.

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