RESUMEN

BACKGROUND: The aspartic proteinase renin plays an important physiological role in the regulation of blood pressure. It catalyses the first step in the conversion of angiotensinogen to the hormone angiotensin II. In the past, potent peptide inhibitors of renin have been developed, but none of these compounds has made it to the end of clinical trials. Our primary aim was to develop novel nonpeptide inhibitors. Based on the available structural information concerning renin-substrate interactions, we synthesized inhibitors in which the peptide portion was replaced by lipophilic moieties that interact with the large hydrophobic S1/S3-binding pocket in renin. RESULTS: Crystal structure analysis of renin-inhibitor complexes combined with computational methods were employed in the medicinal-chemistry optimisation process. Structure analysis revealed that the newly designed inhibitors bind as predicted to the S1/S3 pocket. In addition, however, these compounds interact with a hitherto unrecognised large, distinct, sub-pocket of the enzyme that extends from the S3-binding site towards the hydrophobic core of the enzyme. Binding to this S3(sp) sub-pocket was essential for high binding affinity. This unprecedented binding mode guided the drug-design process in which the mostly hydrophobic interactions within subsite S3(sp) were optimised. CONCLUSIONS: 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.

Asunto(s)

Antihipertensivos/síntesis química , Antihipertensivos/farmacología , Diseño de Fármacos , Inhibidores de Proteasas/síntesis química , Inhibidores de Proteasas/farmacología , Renina/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , Angiotensinógeno/análogos & derivados , Animales , Antihipertensivos/química , Antihipertensivos/metabolismo , Sitios de Unión/fisiología , Callithrix , Cristalografía por Rayos X , Humanos , Enlace de Hidrógeno/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/fisiopatología , Ratones , Modelos Moleculares , Estructura Molecular , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Unión Proteica/fisiología , Conformación Proteica , Renina/metabolismo , Relación Estructura-Actividad , Especificidad por Sustrato

RESUMEN

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.

Asunto(s)

Renina/antagonistas & inhibidores , Aminoácidos , Animales , Presión Sanguínea/efectos de los fármacos , Callitrichinae , Catepsina D/antagonistas & inhibidores , Fenómenos Químicos , Química , Dipéptidos , Perros , Humanos , Pepsina A/antagonistas & inhibidores , Renina/sangre , Relación Estructura-Actividad , Sulfonas

RESUMEN

Crystalline nickel(II) and dicyanocobalt(III) complexes of a racemic 1,2,2,7,7,12,12,17,17,20-decamethyl-20-hydroxy-1,2,3,7,8,12,13,20-octahydro- 17H-porphyrin rearrange to the corresponding complexes of racemic 19-acetyl-1,2,2,7,7,12,12,17,17-nonamethyl-trans-corrin on melting (approximately 290 degrees C and 260 degrees C, respectively). The nickel(II) 19-acetylcorrinate formed in this way is shown to deacetylate to racemic nickel(II) 1,2,2,7,7,12,12,17,17-nonamethyl-trans-corrinate on treatment with 2 M KOH. These reactions are being studied as potentially biomimetic chemical models for the elusive ring contraction step in vitamin B(12) biosynthesis.