Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 10(-8)M. Esterification or amidification of the carboxyl group of the C-terminal statine did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied.
The synthesis of new [(dialkylamino)alkyl]pyridylacetamides is reported. These compounds displayed a potent antiarrhythmic activity, as demonstrated on a model of myocardial infarction in the conscious dog. Structure-activity relationships are discussed within a series of 22 homologues, comparing relative antiarrhythmic properties and cardiac side effects. One of these compounds, 15, has been selected as a candidate for clinical evaluation in man. Among derivatives of 2-(2-pyridyl)butyramides, 4-(dialky lamino)-2-phenyl-2-(2-pyridyl)butyr amides have been found to possess antiarrhythmic activity. The leading compound in this class, disopyramide (DP, 1), is active in Scheme I (Q5-CH.C» ^(03-C-CR4R5 CN 4 H2, Pd/C CHCN base/CICH2CH2N(R2R3) CCH2CH2N(R2R3) CN H2SO4 O C0NH2 CCH2CH2NCCH(CH3)2]2(1) R.
20 Analoge (Ib)‐(VII) von Somatostatin (Ia) mit Taurin, Azaalanin und D‐Aminosäuren als Bausteinen oder mit fehlenden Bausteinen werden teils nach der Fragmentkondensationsmethode [(Ib)‐(IVb)], teils nach dem Festphasen‐Verfahren ‐ durch schrittweisen Aufbau vom C‐terrninalen Cys‐ Rest aus ‐ synthetisiert, um möglicherweise Verbindungen mit größerer spezifischer Wirksamkeit (Hemmung der Freisetzung von Insulin oder Glucagon) zu gewinnen.
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