Peptidomimetic aminomethylene ketone inhibitors of interleukin-1 beta-converting enzyme (ICE).

Pyridone-based peptidomimetic inhibitors of recombinant human Interleukin-1 beta-converting enzyme (ICE, caspase-1) with an aminomethylene ketone activating group in the P1' position are described. Several analogues with sub-nanomolar Ki's versus ICE and improved aqueous solubility are reported.

Synthesis and biological activity of potent, low molecular weight renin inhibitors.

A series of renin inhibitors containing the dipeptide transition state mimics (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Ala) and (2R,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexyl hexanoic acid (Cha-psi[CH(OH)CH2]Val) were prepared. A structure-activity study, using pseudopeptide (Boc-Phe-His-Leu-psi[CH(OH)CH2]Val-Ile-His-OH) as our lead structure, led to a new series of inhibitors, which correspond to tripeptides and contain no natural amino acids. For example, R,S-Bpma-Ape-Cha-psi[CH(OH)CH2]Ala-NH2 (IC50 = 1.

Potent in vivo inhibitors of rat renin: analogues of human and rat angiotensinogen sequences containing different classes of pseudodipeptides at the scissile site.

Using solid-phase methodology we have synthesised peptides based on the 8-14 or 6-14 human and rat angiotensinogen sequences, containing the following different isosteric units at the P1-P1' cleavage site: Leu-psi[CH2NH]Leu; Leu-psi[CH(OH)CH2]Val; Leu-psi[CH(OH)CH2]Leu and Leu-psi[CH(NH2)CH2]Val. In vitro, peptide Piv-His-Pro-Phe-His-Leu-psi[CH(OH)CH2]Leu-Tyr-Tyr-Ser-NH2(XXI) is the most potent inhibitor of rat plasma renin reported having an IC50 of 0.21 nM; it is a much weaker inhibitor of human renin (IC50 45 nM).

New renin inhibitors containing novel analogues of statine.

Solid-phase methodology has been used to synthesize a series of peptides based on the N-terminal sequence of human angiotensinogen in which statine (Sta) or the novel analogues (3S,4S)-3,4-diamino- or (3R,4S)-3,4-diamino-6-methylheptanoic acid (Ads or R-Ads) and (3S,4S)-4-amino-3-aminomethyl- or (3R,4S)-4-amino-3-aminomethyl-6-methylheptanoic acid (Amd or R-Amd) replace either residue 10 or both residues 10-11 at the P1-P1' cleavage site. The synthesis of these novel analogues of statine together with biological results on the inhibition of human and rat renin by peptides derived from them is reported. The absolute stereochemistry of the (3S,4S) Ads was determined by an X-ray crystallographic analysis of its N gamma-Boc, B beta-Z, R(+)-1-methyl benzamide derivative.

(3R)-N-(1-(tert-butylcarbonylmethyl)-2,3-dihydro-2-oxo-5-(2-pyridyl)-1H-1,4-benzodiazepin-3-yl)-N'-(3-(methylamino)phenyl)urea (YF476): a potent and orally active gastrin/CCK-B antagonist.

A number of new 1,4-benzodiazepin-2-one-based gastrin/CCK-B receptor antagonists related to the archetypal analogue L-365,260, and more closely to the recently reported compound YM022, have been synthesized and evaluated for biological activity. The compounds were screened for their ability to inhibit the binding of [125I]CCK-8 to gastrin/CCK-B receptors prepared from rat brains and that of [3H]L-364,718 to CCK-A receptors from rat pancreas, and were shown to be potent and selective ligands for the gastrin/CCK-B receptor. Functional studies in vivo demonstrated the compounds to be antagonists of the receptor as evidenced by their ability to inhibit pentagastrin-induced gastric acid secretion in anesthetized rats.