Discovery of a Novel Class of Selective Non-Peptide Antagonists for the Human Neurokinin-3 Receptor. 2. Identification of (S)-N-(1-Phenylpropyl)-3-hydroxy-2- phenylquinoline-4-carboxamide (SB 223412) (original) (raw)
Related papers
Journal of Medicinal Chemistry, 1997
Optimization of the previously reported 2-phenyl-4-quinolinecarboxamide NK-3 receptor antagonist 14, with regard to potential metabolic instability of the ester moiety and affinity and selectivity for the human neurokinin-3 (hNK-3) receptor, is described. The ester functionality could be successfully replaced by the ketone (31) or by lower alkyl groups (Et, 21, or n-Pr, 24). Investigation of the substitution pattern of the quinoline ring resulted in the identification of position 3 as a key position to enhance hNK-3 binding affinity and selectivity for the hNK-3 versus the hNK-2 receptor. All of the chemical groups introduced at this position, with the exception of halogens, increased the hNK-3 binding affinity, and compounds 53 (3-OH, SB 223412, hNK-3-CHO binding K i) 1.4 nM) and 55 (3-NH 2 , hNK-3-CHO binding K i) 1.2 nM) were the most potent compounds of this series. Selectivity studies versus the other neurokinin receptors (hNK-2-CHO and hNK-1-CHO) revealed that 53 is about 100-fold selective for the hNK-3 versus hNK-2 receptor, with no affinity for the hNK-1 at concentrations up to 100 µM. In vitro studies demonstrated that 53 is a potent functional antagonist of the hNK-3 receptor (reversal of senktide-induced contractions in rabbit isolated iris sphincter muscles and reversal of NKB-induced Ca 2+ mobilization in CHO cells stably expressing the hNK-3 receptor), while in vivo this compound showed oral and intravenous activity in NK-3 receptor-driven models (senktide-induced behavioral responses in mice and senktide-induced miosis in rabbits). Overall, the biological data indicate that (S)-N-(1-phenylpropyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (53, SB 223412) may serve as a pharmacological tool in animal models of disease to assess the functional and pathophysiological role of the NK-3 receptor and to establish therapeutic indications for non-peptide NK-3 receptor antagonists.
Journal of Medicinal Chemistry, 1996
Pharmacological and molecular biological studies indicate the existence of at least three human tachykinin receptor subtypes, designated neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3), 1-3 which belong to the superfamily of G-protein-coupled receptors possessing seven transmembrane domains. 4 The endogenous ligands for these receptors constitute a family of small neuropeptides, named tachykinins or neurokinins, which share the common carboxy-terminal region Phe-X-Gly-Leu-MetNH 2 . The main mammalian tachykinins, substance P, neurokinin A (NKA), and neurokinin B (NKB), interact with all three tachykinin receptors, although there is a defined agonist rank order of potency for NK-1, NK-2, and NK-3 receptors, respectively; for example, for the NK-3 receptor the rank potency order is NKB > NKA > substance P.
N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists II
Bioorganic & Medicinal Chemistry Letters, 2006
Introduction of selected amine containing side chains into the 3-position of N 0 ,2-diphenylquinoline-4-carbohydrazide based NK 3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI Kr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ 90 7 mg/kg po; plasma Occ 90 0.4 lM) and has good selectivity and excellent PK properties.
N′,2-Diphenylquinoline-4-carbohydrazide based NK3 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2006
Introduction of selected amine containing side chains into the 3-position of N 0 ,2-diphenylquinoline-4-carbohydrazide based NK 3 antagonists abolishes unwanted hPXR activation. Introduction of a fluorine at the 8-position is necessary to minimize unwanted hI Kr affinity and a piperazine N-tert-butyl group is necessary for metabolic stability. The lead compound (8m) occupies receptors within the CNS following oral dosing (Occ 90 7 mg/kg po; plasma Occ 90 0.4 lM) and has good selectivity and excellent PK properties.
Recent advances in neurokinin-3 receptor antagonists
Expert Opinion on …, 2000
This review addresses the recent highlights and progress made in the neurokinin-3 (NK-3) receptor area since the last update, provided in this journal in 1997. Whereas in the neurokinin-1 (NK-1) and neurokinin-2 (NK-2) biological areas literature information based on clinical data account for a high therapeutic potential (in emesis and depression for NK-1 and asthma for NK-2 receptor antagonists), there is a total deficiency of information from NK-3 receptor antagonists in clinical development. No other chemical classes in addition to dichlorophenylalkylpiperidines, represented by SR 142,801 and quinolines, represented by SB-222200 and SB-223412, have been identified by pharmaceutical companies and scientists involved in the specific field. Biological evidence indicates pain/inflammation as a suitable CNS-related therapeutic target, this conclusion is based on localisation studies and efficacy of selected NK-3 receptor antagonists in rat disease models of inflammatory pain. In the periphery, the most likely therapeutic indications might be pulmonary and gastrointestinal tract diseases. It is clearly still premature to anticipate any therapeutic potential in man.
Highly potent and selective heptapeptide antagonists of the neurokinin NK-2 receptor
Journal of Medicinal Chemistry, 1992
Incorporation of pro^ into substance P related peptides is known to enhance neurokinin NK-2 receptor agonist potency and selectivity with respect to other neurokinin receptors. We now report that replacement of D-w g by D-Pros in the nonselective neurokinin antagonist [Ar$,~-Trp'*~, Nle"1-SP(5-11) gave a partial agonist with NK-2 receptor selectivity. Further incorporation of Prolo provided the weak but selective NK-2 antagonist Arg-Ala-D-Trp-Phe-~-Pro-Pro-Nle-NH~ (compound 4; NK-2 PKB = 5.9; NK-1 PKB = 4.7; NK-3 PKB < 4.6). Addition of a suitable lipophilic N-terminal substituent (e.g. Boc, PhCO, cyclohexylcarbonyl) to this compound greatly enhanced NK-2 antagonist activity (compound 10, GR 83074; NK-2 PKB = 8.21, and combined with further optimization of the N-terminal amino acids, provided the extremely potent and selective NK-2 antagonist PhCO-Ala-Ala-D-Trp-Phe-~Pro-Pro-Nle-NH~ (compound 34, GR 94800; NK-2 PKB = 9.6; NK-1 PKB = 6.4; NK-3 pKB = 6.0). Compounds of this class produced a potent inhibition of NK-2 agonisbinduced bronchoconstriction in the anaesthetized guinea-pig.
Possible Mechanism of Action of Neurokinin-1 Receptors (NK1R) Antagonists
Recently, NK1R (Neurokinin-1 receptors) take attention as new and promising target in anticancer drug development area. It has been proved that non-peptide NK1R antagonists L-733,060, aprepitant and L-732,138 inhibited tumor growth in several cancer cell lines. For the development of novel NK1R antagonists as antitumor agents, heterocyclic compounds which were previously synthesized by our team, tested for their cytotoxic activities in several cancer cell lines in this study. Among the tested compounds, a benzothiazole derivative BSN-009 inhibited colon cancer cell lines growth by 57.53% by comparing the activity to the control drug aprepitant. Molecular modeling studies such as molecular docking and pharmacophore generation were performed with known NK1R antagonists and BSN-009 by using Discovery Studio 3.5 in order to explain their binding modes to NK1R. BSN-009 may be a good anticancer drug candidate as a possible NK1R antagonist and is worthy to carry on the anticancer studies.
Journal of Medicinal Chemistry, 1999
Steric and electrostatic requirements at position 6 of [Nle 10 ]NKA(4-10), a full agonist of NK-2 receptors, for molecular recognition by the receptor were studied. Two series of peptide analogues, (a) p-substituted analogues, [p-X-Phe 6 ,Nle 10 ]NKA(4-10), where X) F, Cl, Br, I, NH 2 , NO 2 , and (b) [D-Phe 6 ,Nle 10 ]NKA(4-10), [Trp 6 ,Nle 10 ]NKA(4-10), and [Chex-Ala 6 ,Nle 10 ]-NKA(4-10), were synthesized, and their biological activity was examined. Competition binding experiments with [ 3 H]NKA were performed using cloned human NK-2 receptors expressed in CHO cells. Antagonistic and agonistic properties of the analogues were studied using an in vitro functional assay with hamster tracheal rings. The rank order of potency of agonists was [Nle 10 ]NKA(4-10) ≈ [p-F-Phe 6 ,Nle 10 ]NKA(4-10) > [p-NH 2-Phe 6 ,Nle 10 ]NKA(4-10) > [p-Cl-Phe 6 ,-Nle 10 ]NKA(4-10) > [p-NO 2-Phe 6 ,Nle 10 ]NKA(4-10) > [Trp 6 ,Nle 10 ]NKA(4-10). Size and planarity of the aromatic side chain were crucially important for the biological activity, whereas electrondonating and electron-withdrawing properties of the para-substituent were less important. The results favor the hypothesis that weakly polar π-π interactions exist between the aromatic group and the receptor.
Identification of a new series of non-peptidic NK3 receptor antagonists
Bioorganic & Medicinal Chemistry Letters, 2011
The identification and structure-activity relationships of 2-aminomethyl-1-aryl cyclopropane carboxamides as novel NK 3 receptor antagonists are reported. The compound series was optimized to give analogues with low nanomolar binding to the NK 3 receptor and brain exposure, leading to activity in vivo in the senktide-induced hypoactivity model in gerbils.