No abstract

Our design approach led to compounds with high in vitro affinity and specificity for renin, favourable bioavailability and excellent oral efficacy in lowering blood pressure in primates. These renin inhibitors are therefore potential therapeutic agents for the treatment of hypertension and related cardiovascular diseases.

The action of renin is the rate-limiting step of the renin-angiotensin system (RAS), a key regulator of blood pressure. Effective renin inhibitors directly block the RAS entirely at source and, thus, may provide a vital weapon for hypertension therapy. Our efforts toward identifying novel small-molecule peptidomimetic renin inhibitors have resulted in the design of transition-state isosteres such as 1 bearing an all-carbon 8-phenyl-octanecarboxamide framework. Optimization of the extended P3 portion of 1 and extensive P2' modifications provided analogues with improved in vitro potencies in the presence of plasma. X-ray resolution of rh-renin/38a in the course of SAR work surprisingly unveiled the exploitation of a previously unexplored pocket (S3sp) important for strong binding affinities. Several inhibitors demonstrated oral efficacy in sodium-depleted marmosets. The most potent, 38a, induced dose-dependently a pronounced reduction in mean arterial blood pressure, paralleled by complete blockade of active plasma renin, up to 8 h post-dose. Oral bioavailability of 38a was 16% in marmosets.

A series of renin inhibitors containing the dipeptide transition state mimics (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-7-methyloctanoic acid (Leu (OH)/Val) and (2S,4S,5S)-5-amino-4-hydroxy-2-isopropyl-6-cyclohexylhexanoic acid (CHa /(OH)/Val) was prepared. A structure-activity study with Boc-Phe-His-Leu (OH)/Val-Ile-His-NH2 (8a) as starting material led to N-[(2S)-2-[(tert-butylsulfonyl)methyl]-3-phenylpropionyl]-His-Cha (OH)/ Val- NHC4H9-n (8i) which has the length of a tetrapeptide and contains only one natural amino acid. Compound 8i had an IC50 of 2 x 10(-9) M against human renin and showed high enzyme specificity; IC50 values against the related aspartic proteinases pepsin and cathepsin D were (8 x 10(-6) and 3 x 10(-6) M, respectively). In salt-depleted marmosets, 8i inhibited plasma renin activity PRA and lowered blood pressure for up to 2 h after oral administration of a dose of 10 mg/kg.

clo[6.1 .O]nonatriene has been interpreted by a participation of an aromatic transition state. The ca. 7 kcal/mol lower Gibbs activation energy of ( l a ) -(24 would accordingly suggest an aromatic transition state for the bicyclopentene rearrangement. We assume, however, that the lower activation barrier of the bicyclopentene rearrangement does not only result from the resonance stabilization of the transition state, but largely from the high ground-state enthalpy of the bicyclopentene system. The heat of hydrogenation of the olefink double bond in the parent compound, bicy-cl0[2.1 .O]pent-2-ene (25 "C: A H = 42.5 kcal/mol) is higher by ca. 9 kcal/mol than that of the double bond in bicyclo[2.2.0]hex-2-ene and bicycl0[3.2.0]hept-6-ene~~~. The additional energy content of 9 kcal/mol is attributed to an antiaromatic destabilization of the bicyclo[2.1.0]pent-2-ene ground state and must be considered for estimating the resonance stabilization of the transition state of the "walk" rearrangement (la) -+ (2a). . Lemal, ibid. 99, 629 (1 977). [2] a) M. C. Flowers, H. M. Frey, J. Am. Chem. Soc. 94, 8636 (1972); b) W. E. Farneth, M. B. D'Amore, J. I. Brauman, ibid. 98, 5546 (1976); c) G. D. And r e w J. E. Buldn,in, ibid. 99. 4853 (1977), references cited therein; d) ibid. 99, 4851 (1977).[3l (4) and (5) were prepared analogously to the procedure for (6) (H. Muller, G.

No abstract

Crystalline nickel(II) and dicyanocobalt(Ill) corm-COH COOH plexes of a racemic 1,2,2

Professor George Biichi zurn 60. Geburtstag gewidmet