1 The pharmacological properties of the novel diarylacetamide .c-opioid receptor agonist, EMD 61753, have been compared with those of ICI 197067 (a centrally-acting K agonist) and ICI 204448 (a peripherally-selective Kc agonist).2 EMD 61753 binds with high affinity (IC50 5.6 nM) and selectivity (K:ft:6:a binding ratio 1:536:125:> 1,786) to ic-opioid receptors and is a full and potent (IC50 54.5 nM) agonist in an in vitro assay for K-opioid receptors (rabbit vas deferens preparation). 3 Systemically-applied ['4C]-EMD 61753 is found in high concentrations in the lungs, liver, adrenal glands and kidneys. Considerably less radioactivity is detected in the whole brain, and this radioactivity is concentrated in the region of the cerebral ventricles in the choroid plexuses. EMD 61753 penetrates only poorly into the CNS. 4 EMD 61753 was weakly effective in pharmacological tests of central activity. This compound reversed haloperidolol-induced DOPA accumulation in the nucleus accumbens of the rat only at a dose of 30mgkg-', s.c., (doses of 0.1, 1.0 and 10mgkg-', s.c., and 1.0, 10 and 100mgkg-', p.o., were inactive). Hexobarbitone-induced sleeping in mice was prolonged by EMD 61753 at threshold doses of 10 mg kg-', s.c., and 100 mg kg-', p.o., whereas the motor performance of rats in the rotarod test was impaired by EMD 61753 with an IDm, value of 453 mg kg-', s.c.5 EMD 61753 produced dose-dependent, naloxone-reversible antinociception in the mouse formalin test (1st phase ID50 1.9 mg kg-', s.c., and 10.4mg kg-', p.o.; 2nd phase IDm 0.26mg kg', s.c., and 3.5 mg kg-', p.o.) and rodent abdominal constriction test (ID50 mouse 1.75 mg kg-', s.c., and 8.4mg kg-', p.o.; IDs rat 3.2mg kg', s.c., and 250mg kg', p.o.). EMD 61753 was inactive, or only weakly effective, in the rat pressure test under normalgesic conditions. After the induction of hyperalgesia with carrageenin, however, this compound elicited potent, dose-dependent (IDs 0.08 mg kg-', s.c., and 6.9 mg kg-', p.o., after remedial application, and 0.2 mg kg-', s.c., and 3.1 mg kg-', p.o., after prophylactic application) and naloxone-reversible antinociception. The antinociceptive action of systemically-applied (50 mg kg-', p.o.) EMD 61753 in the hyperalgesic pressure test was completely inhibited by injection of the K-opioid antagonist norbinaltorphimine (100 Lg) into the inflamed tissue, a result which indicates that this opioid effect is mediated peripherally. 6 Cutaneous plasma protein extravasation produced by antidromic electrical stimulation of the rat saphenous nerve was dose-dependently inhibited by systemically-applied EMD 61753 (ID13 values 3.7 mg kg', s.c., and 35.8 mg kg', p.o.), and this effect was completely antagonized by intraplantar application of norbinaltorphimine (50 pg). Extravasation elicited by the intraplantar application of substance P (10 pg) was not influenced by the administration of EMD 61753.7 EMD 61753 produced dose-dependent diuresis in non-hydrated rats at doses of and above 1.0 mg kg-', s.c., and 10 mg kg-', p.o., and in saline-loaded ra...

Incorporation of beta-alanine or gamma-aminobutyric acid in position P2 of ACHPA or Leu psi [CHOHCH2]Val-based tetrapeptides gave highly active renin inhibitors (compounds V, VI, and XVII) with high specificity for renin and a remarkable stability against chymotrypsin. Replacement of the amide bond between P2 and P3 by isosteres (ketomethylenes, hydroxyethylenes, and the corresponding thio-insertion analogues) led to compounds (VIII-XIII, XVIII, and XIX) with renin inhibitory activity in the nanomolar range. Oral activity was achieved by incorporation of polar functionalities at the N-terminus of beta-alanine-containing tetrapeptides. One of these compounds (XXVIII) was chosen for further studies. This inhibitor demonstrated excellent efficacy and a long duration of action after intravenous and oral administration to cynomolgus monkeys.

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A series of novel renin inhibitors containing 2-(((3-phenylpropyl)phosphoryl)oxy)alkanoic acid moieties as P2-P3 surrogates are presented. The P2-P3 mimetics were obtained from (omega-phenylalkyl)-phosphinic acids 1a-c and 2-hydroxyalkanoic acid benzyl esters 2a-f by N,N'-dicyclohexylcarbodiimide-mediated coupling and subsequent oxidation with sodium metaperjodate. Ester cleavage of these derivatives and coupling with P1-P1' transition-state mimetics I-VII provided highly selective compounds with inhibitory potencies in the lower nanomolar range. Small renin inhibitors, such as analogues 8c and 8h with molecular weights of 539 and 537, respectively, could be prepared. These compounds exhibited IC50 values of about 20 nM against human plasma renin. Compound 7i was examined in vivo for its hypotensive effect. In salt-depleted cynomolgus monkeys, 7i inhibited plasma renin activity almost completely and lowered blood pressure after oral administration of a dose of 30 mg/kg.

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