- Structural Factors Affecting the Basicity of ω-Pyridylalkanols, ω-Pyridylalkanamides and ω-Pyridylalkylamines
-
The present paper describes the preparation by conventional methods (when not available commercially) and the pKa-determination of the α-, β- and γ-isomers of pyridylethanamide, 3-pyridylpropanamide, 4-pyridylbutanamide, 5-pyridylpentanamide, pyridylmethanol, 2-pyridylethanol, 3-pyridylpropanol, 4-pyridylbutanol, 5-pyridylpentanol, pyridylmethylamine, 2-pyridylethylamine, 3-pyridylpropylamine, 4-pyridylbutylamine, and 5-pyridylpentylamine.While a field effect accounts for many variations in pKa as a function of chain length, marked inductive effects are operative in some methyl and ethyl homologs.The pKa-decreasing influence of an intramolecular H-bond is also apparent in some lower homologs belonging to the α-series.
- Mayer, Joachim M.,Testa, Bernard
-
-
Read Online
- Structure-based evolution of subtype-selective neurotensin receptor ligands
-
Subtype-selective agonists of the neurotensin receptor NTS2 represent a promising option for the treatment of neuropathic pain, as NTS2 is involved in the mediation of m-opioid-independent anti-nociceptive effects. Based on the crystal structure of the subtype NTS1 and previous structure-activity relationships (SARs) indicating a potential role for the sub-pocket around Tyr11 of NT(8-13) in subtype-specific ligand recognition, we have developed new NTS2-selective ligands. Starting from NT(8-13), we replaced the tyrosine unit by β2-amino acids (type 1), by heterocyclic tyrosine bioisosteres (type 2) and peptoid analogues (type 3). We were able to evolve an asymmetric synthesis of a 5-substituted azaindolylalanine and its application as a bioisostere of tyrosine capable of enhancing NTS2 selectivity. The S-configured test compound 2a, [(S)-3-(pyrazolo[1,5-α]pyridine-5-yl)-propionyl11]NT(8-13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30-fold NTS2 selectivity over NTS1. The (R)-epimer 2b showed lower NTS2 affinity but more than 600-fold selectivity over NTS1.
- Schaab, Carolin,Kling, Ralf Christian,Einsiedel, Jürgen,Hübner, Harald,Clark, Tim,Seebach, Dieter,Gmeiner, Peter
-
p. 206 - 208
(2015/03/04)
-
- Structure-Based Evolution of Subtype-Selective Neurotensin Receptor Ligands
-
Subtype-selective agonists of the neurotensin receptor NTS2 represent a promising option for the treatment of neuropathic pain, as NTS2 is involved in the mediation of μ-opioid-independent anti-nociceptive effects. Based on the crystal structure of the subtype NTS1 and previous structure-activity relationships (SARs) indicating a potential role for the sub-pocket around Tyr11 of NT(8-13) in subtype-specific ligand recognition, we have developed new NTS2-selective ligands. Starting from NT(8-13), we replaced the tyrosine unit by β2-amino acids (type 1), by heterocyclic tyrosine bioisosteres (type 2) and peptoid analogues (type 3). We were able to evolve an asymmetric synthesis of a 5-substituted azaindolylalanine and its application as a bioisostere of tyrosine capable of enhancing NTS2 selectivity. The S-configured test compound 2a, [(S)-3-(pyrazolo[1,5-a]pyridine-5-yl)-propionyl11]NT(8-13), exhibits substantial NTS2 affinity (4.8 nm) and has a nearly 30-fold NTS2 selectivity over NTS1. The (R)-epimer 2b showed lower NTS2 affinity but more than 600-fold selectivity over NTS1. Tyrosine surrogates: Peptides 2a,b showed that the 5-substituted azaindolylalanine is an appropriate bioisostere of tyrosine capable of enhancing NTS2 selectivity. Compound 2a exhibits single-digit nanomolar affinity (4.8 nm) and a nearly 30-fold NTS2 selectivity over NTS1.
- Schaab, Carolin,Kling, Ralf Christian,Einsiedel, Jürgen,Hübner, Harald,Clark, Tim,Seebach, Dieter,Gmeiner, Peter
-
p. 206 - 218
(2015/08/24)
-
- SPIROHYDANTOIN COMPOUNDS AND THEIR USE AS SELECTIVE ANDROGEN RECEPTOR MODULATORS
-
The present invention relates to a compound of formula (1-1 ) in free form or in pharmaceutically acceptable salt form in which the substituents are as defined in the specification; to its preparation, to its use as a medicament and to medicaments comprising it. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.
- -
-
Page/Page column 68
(2013/09/12)
-
- From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3
-
Highly potent and selective substrate analogue factor Xa inhibitors were obtained by incorporation of non-basic or modestly basic P1 residues known from the development of thrombin inhibitors. The modification of the P2 and P3 amino acids strongly influenced the selectivity and provided potent dual factor Xa and thrombin inhibitors without affecting the fibrinolytic enzymes. Several inhibitors demonstrated excellent anticoagulant efficacy in standard clotting assays in human plasma.
- Doennecke, Daniel,Schweinitz, Andrea,Stuerzebecher, Anne,Steinmetzer, Peter,Schuster, Maj,Stuerzebecher, Uta,Nicklisch, Silke,Stuerzebecher, Joerg,Steinmetzer, Torsten
-
p. 3322 - 3329
(2008/02/08)
-
- Secondary amides of sulfonylated 3-amidinophenylalanine. New potent and selective inhibitors of matriptase
-
Matriptase is an epithelium-derived type II transmembrane serine protease and has been implicated in the activation of substrates such as pro-HGF/SF and pro-uPA, which are likely involved in tumor progression and metastasis. Through screening, we have identified bis-basic secondary amides of sulfonylated 3-amidinophenylalanine as matriptase inhibitors. X-ray analyses of analogues 8 and 31 in complex with matriptase revealed that these inhibitors occupy, in addition to part of the previously described S4-binding site, the cleft formed by the molecular surface and the unique 60 loop of matriptase. Therefore, optimization of the inhibitors included the incorporation of appropriate sulfonyl substituents that could improve binding of these inhibitors into both characteristic matriptase subsites. The most potent derivatives inhibit matriptase highly selective with Ki values below 5 nM. Molecular modeling revealed that their improved affinity results from interaction with the S4 site of matriptase. Analogues 8 and 59 were studied in an orthotopic xenograft mouse model of prostate cancer. Compared to control, both inhibitors reduced tumor growth, as well as tumor dissemination.
- Steinmetzer, Torsten,Schweinitz, Andrea,Stürzebecher, Anne,D?nnecke, Daniel,Uhland, Kerstin,Schuster, Oliver,Steinmetzer, Peter,Müller, Friedemann,Friedrich, Rainer,Than, Manuel E.,Bode, Wolfram,Stürzebecher, J?rg
-
p. 4116 - 4126
(2007/10/03)
-
- Fibrinogen receptor antagonists
-
Fibrinogen receptor antagonists having the structure, for example, of STR1 for example STR2
- -
-
-
- Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs
-
A novel series of potent specific HIV-1 inhibitory compounds is described. The lead compound in the series, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea (1), inhibits HIV-1 RT using rCdG as the template with an IC50 of 0.9 μM. In MT-4 cells, compound 1 inhibits HIV-1 with an ED50 of 1.3 μM. The 50% cytotoxic dose in cell culture is >380 μM. The chemical structure-activity relationship (SAR) was developed by notionally dividing the lead compound in four quadrants. The SAR strategy had two phases. The first phase involved optimization of antiviral activity through independent variation of quadrants 1-4. The second phase involved the preparation of hybrid structures combining the best of these substituents. Further SAR studies and pharmacokinetic considerations led to the identification of N-(2-pyridyl)-N'-(5-bromo-2- pyridyl)-thiourea (62; LY300046 · HCl) as a candidate for clinical evaluation. LY300046 · HCl inhibits HIV-1 RT with an IC50 of 15 nM and in cell culture has an ED50 of 20 nM.
- Bell,Cantrell,Hogberg,Jaskunas,Johansson,Jordan,Kinnick,Lind,Morin Jr.,Noreen,Oberg,Palkowitz,Parrish,Pranc,Sahlberg,Ternansky,Vasileff,Vrang,West,et al.
-
p. 4929 - 4936
(2007/10/03)
-
- New 2-pyridylethylamines with dopaminergic activity: Synthesis and radioligand-binding evaluation
-
In order to determine whether the pyridine nucleus could replace the catechol moiety of the neurotransmitter dopamine or the phenol ring of the dopaminergic pharmacophore m-hydroxyphenylethylamine, the 2-(3-pyridyl)ethylamine 7, 2-(4-pyridyl)ethylamine 8, 2-(2-hydroxy-4-pyridyl)ethylamine 10 and their N,N-di-n-propyl- and N-n-propyl-N-2-phenylethyl derivatives were synthesized. The affinities of the new compounds for D1 and D2 dopamine receptors were evaluated by displacement of [3H]SCH 23390 (D1 selective) and [3H]spiperone (D2 selective) on rat neostriatum sections. The 2-(4-pyridyl)ethylamine 8 and its N,N-di-n-propyl derivative 18 showed the same affinity for the D1 and D2 receptors. Other compounds bound to the D1 receptor with higher affinity than to the D2 receptor. The possibility that the above compounds act as agonists and antagonists at the dopamine D1 and D2 receptors is discussed on the basis of guanosine-5'-triphosphate and Na+ displacement curves.
- Claudi,Cingolani,Giorgioni,Cardellini,Amenta,Polidori
-
p. 415 - 421
(2007/10/02)
-
- PO-Activated Olefination and Conversion of Aldehydes and Ketones to Higher Amines; II. Synthesis of Arylethylamines
-
The transformation of arylcarboxaldehydes and/or - ketones 2 by three different routes into arylethylamines 3 and/or 4 is reported.According to the first route, the intermediate iminophosphonates 9 react through a classical PO-activated olefination.The second and the third involve the rearrangement of the iminophosphonates 9 into the vinylphosphoramidates 12.
- Heymes, A.,Chekroun, I.
-
p. 245 - 249
(2007/10/02)
-
- Process for the preparation of β-cyclo-substituted ethylamines
-
The present invention provides a multistep process for the preparation of β-cyclo-substituted ethylamines of the general formula:- in which AR is a heterocyclic or non-heterocyclic aromatic radical, which is optionally mono- or poly- substituted, wherein said compounds represent a class of intermediates which can be converted to 4,5,6,7-tetrahydro[3,2-C] or [2,3-C]pyridines wherein the latter are useful for anti-inflammatory, vasodilator or blood platelet aggregation inhibition activities.
- -
-
-
