Synthesis and biological activity of the penem antibiotic MEN 10700 and its orally absorbed ester MEN 11505.

The synthesis and biological properties of the new penem antibiotic MEN 10700 (6) and of its selected oral prodrug MEN 11505 (8f) are described. MEN 10700 showed a broad spectrum of activity, with high potency both on Gram-positive and Gram-negative strains. It also exhibited good antibacterial activity toward anaerobes and on strains selected for their resistance to other antibacterial agents (cefotaxime- or ceftazidime-resistant Gram-negative strains, ciprofloxacin-resistant E. coli, extended spectrum beta-lactamase producing and cephalosporinase inducible enterobacteria). MEN 10700 showed a very high stability to enzymatic degradation by renal dehydropeptidase DHP-I. After oral administration in rats of the pivaloyloxymethyl ester prodrug MEN 11505, the relative bioavailability of MEN 10700 was calculated as F=43%.

Design and synthesis of nonpeptide angiotensin II receptor antagonists featuring acyclic imidazole-mimicking structural units.

Extensive molecular modelling studies, including conformational analysis and the comparison of molecular electrostatic potential distributions, wee used to evaluate structural parameters of new antagonists containing acyclic replacements of the N = C-N imidazole region. The synthesis and the biological screening of a series of acyl biphenyltetrazole derivatives were planned and realized to gain an insight into the structure-activity relationships of this unusual class of Angiotensin II antagonists.

Synthesis and renin inhibitory activity of novel angiotensinogen transition state analogues modified at the P(2)-histidine position.

With the aim of finding new renin inhibitors with improved bioavailability properties, two angiotensinogen transition state analogues 1a and 1b, containing a novel unnatural amino acid at the P(2) position, namely the (2R,3S)- and (2S,3S)-2-amino-3-(1,3-dithiolan-2-yl)-3-hydroxypropanoic acid (ADHPA), have been synthesized and tested for human renin inhibitory activity and for chemical and enzymatic stability. Only compound 1a (the S-isomer) possessed a significant activity, which was lower than that of the corresponding histidyl derivative KRI-1314, and combined with a low stability to the gut enzyme chymotrypsin.

N-3-substituted pyrimidinones as potent, orally active, AT1 selective angiotensin II receptor antagonists.

A novel series of nonpeptide angiotensin II (A II) antagonists containing a pyrimidinone ring which carries a C-linked biphenyltetrazole moiety and a carboxyheteroaryl group on the 3-position have been prepared. Their affinity for the AT1 receptor was determined in a binding assay on rat adrenal cortical membranes. The in vivo antihypertensive properties were tested by evaluating the inhibition of the pressor response to A II followed by iv and id administration. Extensive molecular modeling studies, including comparison of molecular electrostatic potential distributions, conformational analysis, and overlays on a computational pharmacophore model of A II, were used to evaluate structural parameters of the new compounds, in comparison to other known A II antagonists (e.g., DUP-753 and SK&F 108566). According to the modeling studies, the introduction of a (carboxyheteroaryl)methyl moiety at the 3-position of the pyrimidinone ring led to derivatives with increased potency. Methyl 2-[[4-butyl-2-methyl-6-oxo-5-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl ]- 4-yl]methyl]-1-(6H)-pyrimidinyl]methyl]-3-thiophenecarboxylate (3k, LR-B/081), one of the most potent compounds in the series (Ki = 1.4 nM), exhibited a marked antihypertensive activity on oral administration to conscious renal hypertensive rats, with long duration of action. It was selected for clinical evaluation in the treatment of hypertension in man.