Much current attention focuses on the renin-angiotensin system in relation to mechanisms controlling blood pressure and renal function. Recent demonstrations (ref. 1, ref. 2 and refs therein) that angiotensin-converting enzyme inhibitors show promising clinical antihypertensive properties have been of particular interest. We now report on the design of a novel series of substituted N-carboxymethyl-dipeptides which are active in inhibiting angiotensin-converting enzyme at nanomolar levels. We suggest that these compounds are transition-state inhibitors and that extensions of this design to other metalloendopeptidases merit further study.

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1 The design origins of the potent non-mercapto angiotensin converting enzyme inhibitors enalaprilat and its mono ethyl ester enalapril are described. 2 Lactam analogues of enalaprilat have provided some insight into the conformation of this inhibitor when it is bound to converting enzyme. 3 X-ray crystallographic studies of a related enzyme/inhibitor complex offer an explanation for the high potency and specificity of these and related inhibitors.

2-(Fluoromethyl)-3-(3,4-dihydroxyphenyl)alanine [alpha-FM-Dopa (I)] causes rapid, time-dependent, stereospecific, and irreversible inhibition of hog kidney aromatic amino acid (Dopa) decarboxylase. The inactivation occurs with loss of both the carboxyl carbon and fluoride from I and results in the stoichimetric formation of a covalent enzyme-inhibitor adduct. The data are consistent with I being a suicide inactivator of the enzyme, and a plausible mechanism for the inactivation process is presented. The inactivation is highly efficient in that there is essentially no enzymatic turnover of I to produce the corresponding amine, 1-(fluoromethyl)-2-(3,4-dihydroxyphenyl)ethylamine [alpha-FM-dopamine (II)]. Amine II is also a potent inactivator of the enzyme. In vivo compound I is found to inactivate both brain and peripheral (liver) Dopa decarboxylase activity. The possible significance of these data with respect to the known antihypertensive effect of I is discussed.

Androgen Biosynthesis Inhibitors between 0(2) and H(l) and a H bond type linkage (albeit a strong one) between 0(3) and H(l).The very strong interactions of this arrangement are partially relieved in 2 ways. As in the KHMal, KHClMal, and maleic acid structures the internal angles of the ring system are strained considerably. The two angles 0(2)-C(l)-C(2) and 0(3)-C(4)-C(3) are not significantly different from each other and average 119°36' ± 42'. Similarly the angles C(l)-C(2)-C(3) and C(2)-C(3)-C(4) are insignificantly different and average 130°24' ± 24'. These angles are however significantly different from their unstrained counterparts of 121°18' and 121°3 0', respec-