337340-02-0Relevant articles and documents
Design and solid-phase synthesis of chiral acyclic and cyclic diamine ligands
Li, Dehe,Hall, Dennis G.
, p. 1733 - 1736 (2005)
A model resin-bound oligoamide functionalized with a rationally designed non-interfering diamine spacer was reduced with borane-THF to provide the corresponding diamine derivative. The latter was transformed using an efficient orthogonal sequence of trans
Triazine dendrimers with orthogonally protected amines on the periphery. Masking amines with Dde and BOC groups provides an alternative to carrying protected alcohols and disulfides through an iterative synthesis
Umali, Alona P.,Crampton, Hannah L.,Simanek, Eric E.
, p. 9866 - 9874 (2008/04/12)
(Chemical Equation Presented) An orthogonally protected dendrimer based on melamine displaying 24 Boc-protected amines (Boc is t-butoxycarbonyl) and 12 Dde-protected (Dde is N-2-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl) amines was synthesized using a
Identification of a novel 4-aminomethylpiperidine class of M3 muscarinic receptor antagonists and structural insight into their M3 selectivity
Sagara, Yufu,Sagara, Takeshi,Uchiyama, Minaho,Otsuki, Sachie,Kimura, Toshifumi,Fujikawa, Toru,Noguchi, Kazuhito,Ohtake, Norikazu
, p. 5653 - 5663 (2007/10/03)
Identification of a novel class of potent and highly selective M 3 muscarinic antagonists is described. First, the structure-activity relationship in the cationic amine core of our previously reported triphenylpropionamide class of M3 selective antagonists was explored by a small diamine library constructed in solid phase. This led to the identification of M3 antagonists with a novel piperidine pharmacophore and significantly improved subtype selectivity from a previously reported class. Successive modification on the terminal triphenylpropionamide part of the newly identified class gave 14a as a potent M3 selective antagonist that had > 100-fold selectivity versus the M1, M 2, M4, and M5 receptors (M3: K i = 0.30 nM, M1/M3 = 570-fold, M 2/M3 = 1600-fold, M4/M3 = 140-fold, M5/M3 = 12000-fold). The possible rationale for its extraordinarily higher subtype selectivity than reported M3 antagonists was hypothesized by sequence alignment of multiple muscarinic receptors and a computational docking of 14a into transmembrane domains of M3 receptors.
Design and synthesis of novel biologically active thrombin receptor non-peptide mimetics based on the pharmacophoric cluster Phe/Arg/NH2 of the Ser42-Phe-Leu-Leu-Arg46 motif sequence: Platelet aggregation and relaxant activities
Alexopoulos, Kostas,Fatseas, Panagiotis,Melissari, Euthemia,Vlahakos, Demetrios,Roumelioti, Panagiota,Mavromoustakos, Thomas,Mihailescu, Stefan,Paredes-Carbajal, Maria Christina,Mascher, Dieter,Matsoukas, John
, p. 3338 - 3352 (2007/10/03)
The identification of the thrombin receptor has promoted the interest for the development of new therapeutic agents capable of selectively inhibiting unwanted biological effects of thrombin on various cell types. In this study we have designed and synthesized two series of new thrombin receptor antagonists based on the thrombin receptor motif sequence S42FLLR46, one possessing two (Phe/Arg) pharmacophoric groups and the other possessing three (Phe/Arg/NH 2). N-(6-Guanidohexanoyl)-N′-(phenylacetyl)piperazine (1), N-(phenylacetyl)-4-(6-guanidohexanoyl-amidomethyl)piperidine (2), and N-(phenylacetyl)-3-(6-guanidohexanoylamido)pyrrolidine (3) (group A) carry the two pharmacophoric side chains of Phe and Arg residues incorporated on three different templates (piperazine, 4-aminomethylpiperidine, and 3-aminopyrrolidine). Compounds with three pharmacophoric groups (group B) were built similarly to group A using the same templates with the addition of an extra methylamino group leading to (S)-N-(6-guanidohexanoyl)-N′ -(2-amino-3-phenylpropionyl)piperazine (4), (S)-N-(2-amino-3-phenylpropionyl)-4-(6-guanidohexanoylamidomethyl)piperidine (5), and (S)-N-(2-amino-3-phenylpropionyl)-3-(6-guanidohexanoylamido) pyrrolidine (6). Compounds were able to inhibit thrombin-induced human platelet activation even at low concentrations. In particular, among compounds in group A, compound 3 was found to be the most powerful thrombin receptor activation inhibitor, showing an IC50 of approximately 0.11 mM on platelet aggregation assay. Among compounds in group B, compound 4 was the most powerful to inhibit thrombin-induced platelet aggregation, showing an IC50 of approximately 0.09 mM. All compounds were also found to act as agonists in the rat aorta relaxation assay. Interestingly, the order of potency of these compounds as agonists of the endothelial thrombin receptor was the inverse of the order of potency of the same compounds as antagonists of the platelet thrombin receptor. Such compounds that are causing vasodilation while simultaneously inhibiting platelet aggregation would be very useful in preventing the installation of atherosclerotic lesions and deserve further investigation as potential drugs for treating cardiovascular diseases. The above findings coupled with computational analysis molecular dynamics experiments support also our hypothesis that a cluster of phenyl, guanidino, and amino groups is responsible for thrombin receptor triggering and activation.
