144085-23-4Relevant articles and documents
Design, synthesis, and in vitro activity of peptidomimetic inhibitors of myeloid differentiation factor 88
Fantò, Nicola,Gallo, Grazia,Ciacci, Andrea,Semproni, Mauro,Vignola, Davide,Quaglia, Marco,Bombardi, Valentina,Mastroianni, Domenico,Zibella, M. Pia,Basile, Giancarlo,Sassano, Marica,Ruggiero, Vito,De Santis, Rita,Carminati, Paolo
, p. 1189 - 1202 (2008/09/20)
We describe the design and synthesis of a peptidomimetic library derived from the heptapeptide AC-RDVLPGT-NH2, belonging to the Toll/IL-1 receptor (TIR) domain of the adaptor protein MyD88 and effective in inhibiting its homodimerization. The a
2-SUBSTITUTED PROLINE BIS-AMIDE OREXIN RECEPTOR ANTAGONISTS
-
Page/Page column 35-36, (2008/06/13)
The present invention is directed to 2-substituted proline bis-amide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.
A highly practical RCM approach towards a molecular building kit of spirocyclic reverse turn mimics
Bittermann, Holger,Boeckler, Frank,Einsiedel, Juergen,Gmeiner, Peter
, p. 6315 - 6322 (2008/09/19)
The development of privileged molecular scaffolds efficiently mimicking reverse turn motifs and thus increasing both binding and selectivity and enabling the elucidation of the bio-active conformation of a natural peptide has attracted remarkable interest. The frequent occurrence of proline in various turn patterns initiated the design of proline-based reverse turn mimetics. As a structural hybridization of a highly potent type VI β-turn inducer 1 with saturated spirocyclic lactams 3 efficiently mimicking type II β turns, we developed a versatile synthetic route towards unsaturated spirocyclic lactams of type 2, when Seebach's self-reproduction of chirality methodology was combined with a peptide coupling reaction and Grubbs' ring-closing metathesis. By this means, a variety of model peptides with six- up to nine-membered lactam rings were accessible following a uniform pathway. Introduction of suitably protected templates into solid-phase peptide synthesis gave rise to unsaturated spirocyclic analogues of the naturally occurring neuropeptide neurotensin. Spectroscopic investigations as well as DFT calculations on a high level of theory revealed a remarkable dependence of the reverse-turn inducing potency on the ring size. While the secondary structure of the unsaturated spirocyclic ε-lactam 12 closely agrees with the reference γlactam 3a, the unsaturated δ-lactam 11 serves as an extraordinarily potent β-turn inducer which is even superior to β-lactams of type 3b. The eight-membered unsaturated spirocyclic lactam 13 adopts a conformation almost ideally matching the prerequisites for a canonical type II β turn with the highest stability of the whole series. In contrast, the nine-membered spirolactam 14 represents a scaffold with a high conformational flexibility.
Evaluation of lactam-bridged neurotensin analogues adjusting ψ(Pro 10) close to the experimentally derived bioactive conformation of NT(8-13)
Bittermann, Holger,Einsiedel, Jürgen,Hübner, Harald,Gmeiner, Peter
, p. 5587 - 5590 (2007/10/03)
The neurotensin C-terminal hexapeptide, NT(8-13), which has been found to adopt a β-strand-like conformation while bound to the NT1 receptor, was modified by the introduction of conformational constraints. Synthesis of the four stereoisomeric 4.4-spirolac
Design, synthesis, and dopamine receptor modulating activity of spiro bicyclic peptidomimetics of L-prolyl-L-leucyl-glycinamide
Khalil, Ehab M.,Ojala, William H.,Pradhan, Ashish,Nair, Venugopalan D.,Gleason, William B.,Mishra, Ram K.,Johnson, Rodney L.
, p. 628 - 637 (2007/10/03)
In the present study, the synthesis of the 5.5.6. and 5.6.5. spiro bicyclic lactam PLG peptidomimetics, compounds 3 and 4, respectively, was undertaken. These peptidomimetics were designed to examine the following: (1) the effect that changing the size of
An efficient and high yield method for the N-tert-butoxycarbonyl protection of sterically hindered amino acids
Khalil, Ehab M.,Subasinghe, Nalin L.,Johnson, Rodney L.
, p. 3441 - 3444 (2007/10/03)
An important method for the N-tert-butoxycarbonyl protection of the amino functionality of α-alkylated prolines and other sterically hindered α,α-disubstituted amino acids has been developed in which the lipophilic base tetramethylammonium hydroxide is used to solubilize the otherwise insoluble zwitterionic amino acid in acetonitrile, thereby obviating the need for an aqueous medium.
Design, synthesis, and conformational analysis of a novel spiro-bicyclic system as a type II β-turn peptidomimetic
Genin, Michael J.,Johnson, Rodney L.
, p. 8778 - 8783 (2007/10/02)
A novel highly constrained spiro-bicyclic system (5) has been developed to mimic the type II β-turn, a secondary structural feature found in many bioactive peptides. This system simultaneously restricts three (φ2, ψ2, and φ3) of the four torsion angles that characterize the type II β-turn. As a test of the design, the asymmetric synthesis and conformational analysis of derivative 6 starting from (R)-2-allylproline is reported. Temperature dependent NMR chemical shift studies in CDCl3 suggest that the amide proton of 6 is involved in an intramolecular hydrogen bond. Also, NOE measurements place this hydrogen under the plane of the bicyclic ring system in proper proximity for this hydrogen bond to form with the acetyl carbonyl oxygen. Modeling studies of 6 produced eight minimum-energy conformations with torsion angles close to those of the classical type II β-turn. A comparison of the minimum-energy conformer of this molecule with the classical type II β-turn gave an RMS fit = 0.161 A?.
