The goal of the present study was to characterize the new renin inhibitor Ro 42-5892 in vitro and in vivo. In vitro, Ro 42-5892 inhibited purified human renin and human plasma renin specifically with an IC M of 0.7 nM and 0.8 nM, respectively. In vivo, Ro 42-5892 reduced mean arterial blood pressure in sodium-depleted marmosets and squirrel monkeys with as low a dose as 0.1 nig/kg orally. Higher doses reduced pressure by 30-35 mm Hg in both species. The duration of blood pressure decrease with 3 ing/kg orally was more than 24 hours. Maximal changes of plasma renin activity, immunoreactive angiotensin I, and immunoreactive angiotensin II were observed at 15 minutes. Renin was reduced by 74±31%, angiotensin I by 85±14%, angiotensin II by 89±17%, and immunoreactive active renin was increased by 70±39%. However, unlike pressure, these maximal effects were only transient with complete recovery of renin at 60 minutes under still reduced levels of angiotensin I (61 ±24%) and angiotensin II (71 ±38%) and increased concentrations of active renin (86±30%). The blood pressure lowering was due to specific renin inhibition as exemplified by the influence of the kidney, sodium status, species, or stereoselectivity. Moreover, the reduction of arterial blood pressure was similar to the action of the angiotensin converting enzyme inhibitor cilazapril and was not associated with reflex tachycardia in contrast to the pure vasodilator minoxidil. We conclude that Ro 42-5892 is a potent orally active renin inhibitor acting mainly by inhibition of renin in an extraplasmatic compartment (Hypertension 1991;18:22-31)

A chiral economic synthesis of (R)-and (S)-muscone using the cyclofragmentation of epoxysulfones SummaryStarting with isobutyric acid (2) and using a microbiological oxidation with pseudomonas putida (S)-8-hydroxy-iso-butyric acid (3) has been prepared. Oxidation of 12 with peracid produced a mixture of the two epoxy-sulfones 13 and 14 (cf. scheme 6). The olefin-derivative 24 was oxidized to the corresponding mixture of 25 and 26. A one pot cyclofragmentation (cJ [4] and scheme 6) produced a mixture of (E)-and (Z)-3-methylcyclopentadec-4-en-1-one (13+ 14 --f 15+ 16, 25+ 26 --f 27

1 2 3 6 ) 7 ) G. Stork et nl. beschreiben im Einleitungsformelscheiiia von [12] cinc ilcrartige Fragmcntierungsmoglichkeit. Vgl. &xsichtsarbeiten in [13] und synthetischc Arbcitcn in [141 sowic aucli das schmeizerische Patentgesuch Nr. 12932/75 vom 6. Oktober 1975.

1996 pharmacology, medicinal chemistry, vaccines, serums pharmacology, medicinal chemistry, vaccines, serums V 1100 10 -322 Design and Synthesis of Novel and Potent Monoamine Oxidase Inhibitors. -Starting from the structure of moclobemide (I) novel types of monoamine oxidase inhibitors by bio-isosteric replacement of the amide function by a pyrrole are investigated. -(BRANCA, Q.; JAKOB-ROETNE, R.; KETTLER, R.; ROEVER, S.; SCALONE, M.; Chimia 49 (1995) 10, 381-385; F. Hoffman-La Roche Ltd., CH-4002 Basel, Switz.; EN)

Reversible and selective monoamine oxidase-A inhibitors (RIMA's) like moclobemide (Aurorix®) have rehabilitated the use of MAO inhibitors as drugs of choice in depression. Starting from the structure of moclobemide, we tried to identify novel types of MAO inhibitors by bioisosteric replacement of the amide group. 2-Aminomethyl-5-phenylpyrroles retained some in vitro activity and served as a starting point for the construction of restricted rotation analogues. 3,4-Dihydro-6-phenylpyrrolo[1,2-a]pyrazines were the most interesting members of a family of 6-, 7-, and 8-phenyl-substituted pyrrolo[1,2-a]pyrazines and were subsequently optimized. A 'lipophilic linker' between phenyl and pyrrole ring proved exceedingly useful to improve affinity and led to the benzo[g]pyrazino[1,2-a]indole ring system. Synthetic procedures starting from substituted 1-tetralones allowed the synthesis of substituted derivatives of this ring system. Once the optimal substitution pattern had been identified, facile synthesis of derivatives was achieved from aromatic triflates by Stille or Suzuki coupling. In this series selective and reversible monoamine oxidase-A inhibitors as well as mixed MAO-A and B inhibitors were identified. Affinity of this compounds for MAO was in the nanomolar or even sub-nanomolar range (for monoamine oxidase-A). In conclusion, benzo[g]pyrazino[1,2-a]indoles have been identified as a new class of reversible and highly potent monoamine oxidase inhibitors.