Search

Les reactions electrophiles de l'oxazol-2-yllithium et la synthese de bis-oxazolyl methanol sont reportees

Adenosine is known to exert a wide range of pharmacological effects including hypotension. This effect of adenosine suggested that modified analogues of adenosine might provide useful antihypertensive agents. Thus, we prepared a series of novel N6-benzocycloalkyladenosines and studied their receptor binding and antihypertensive activity. The structure-activity relationship study shows that the adenosine analogues having the hydrophobic phenyl moiety one carbon away from the C6-nitrogen have modest affinity and selectivity for the A1 receptor, whereas those with the phenyl moiety two carbons away from the C6-nitrogen have excellent affinity and selectivity for the A1 receptor. Many of these analogues showed excellent antihypertensive activity with a wide range of effects on heart rate. There is no direct correlation between the receptor binding affinities and antihypertensive activity; however, it is more closely associated with A1 than A2 affinity. The bradycardic effect of these agonists seems to be due to the A1 affinity. From this set, compound 3 was further evaluated in secondary antihypertensive screens. It lowered the blood pressure dose dependently with effects lasting for over 20 h following administration of a 30 mg/kg dose. Compound 3 was also effective in lowering blood pressure in a renal hypertensive rat model. Thus, appropriately modified N6-substituted adenosines represent a novel class of antihypertensive agents.

Enantiomerically pure 2-amino-4-thiazolyl containing amino acids were readily synthesized from commercially available derivatives of aspartic acid and glutamic acid, via reaction with diazomethane and further cyclization with thiourea.

The first total synthesis of WS75624 B, 1 , an endothelin converting enzyme inhibitor produced in a fermentation broth of Saccharothrix sp. No. 75624 is reported herein. WS75624 B is synthesized in 14 steps from commercially available kojic acid, 2 . The synthetic methodology allows for facile substitution at multiple sites on the molecule.

A mirror image phage display approach was used to identify novel and highly specific ligands for Alzheimer's disease amyloid peptide Abeta(1-42). A randomized 12-mer peptide library presented on M13 phages was screened for peptides with binding affinity for the mirror image of Abeta(1-42). After four rounds of selection and amplification the peptides were enriched with a dominating consensus sequence. The mirror image of the most representative peptide (D-pep) was shown to bind Abeta(1-42) with a dissociation constant in the submicromolar range. Furthermore, in brain tissue sections derived from patients that suffered from Alzheimer's disease, amyloid plaques and leptomeningeal vessels containing Abeta amyloid were stained specifically with a fluorescence-labeled derivative of D-pep. Fibrillar deposits derived from other amyloidosis were not labeled by D-pep. Possible applications of this novel and highly specific Abeta ligand in diagnosis and therapy of Alzheimer's disease are discussed.