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Base-promoted cyclization of tert-butyl [2-(benzylideneamino)phenyl]acetate (13a) and subsequent C3-alkylation with allyl bromide affords 3-allyl-2-phenyl-2,3-dihydro-1H-indole-3-carboxylic acid, tert-butyl ester (15b) in high yield as a single diastereomer. This result is contrary to prior publications that describe failed cyclization of an analogous ethyl ester (ethyl [2-(4-methoxybenzylideneamino)phenyl]acetate) under strongly basic conditions. N-Acylation, olefin dihydroxylation, and tert-butyl ester cleavage affords the spirocyclic lactone 18 as a pair of diastereomers. Isolation and characterization of individual diastereomers 18a and 18b are described.

A series of 5-[[1-(4'-carboxybenzyl)imidazolyl]methylidene]hydantoins have been prepared and evaluated as in vitro and in vivo angiotensin II (Ang II) antagonists. Variation of substituents on the hydantoin ring leads to potent and selective Ang II antagonists with nanomolar IC50 values at the AT1 receptor and negligible affinity for the AT2 receptor. Preferred substituents include an n-butyl at R1 and an alkyl or heteroarylmethyl substituent at R2. The selection of the R2 substituent was guided in part by the calculation of its log P since a significant correlation was observed between CLOGP and AT1 binding affinity. The biphenyl tetrazole pharmacophore, common to a number of AT1 antagonists, could be replaced by, for example, a 4-carbomethoxyphenyl substituent resulting in potent Ang II antagonists both in vitro and in vivo. A representative compound of this series is 57, which reduced the mean arterial blood pressure of renal hypertensive rats by 40% at 30 mg/kg po and by 25% at 10 mg/kg po. In addition this compound was efficacious in the salt-deplete normotensive monkey model maximally decreasing blood pressure 27% at 10 mg/kg po. In summary, these compounds belong to a novel class of Ang II antagonists that lack the biphenyl tetrazole moiety yet display appreciable and long lasting oral activity.

Syntheses and structure-activity relationships for a series of substituted tetrahydroisoquinoline-3-carboxylic acid derivatives with AT2-specific angiotensin II receptor binding inhibitory activity are reported.

A novel series of nonpeptide angiotensin II (AII) receptor antagonists containing a 1H-pyrrol-1-yl moiety at the 4-position of the imidazole have been developed. The pyrrole group occupies the same lipophilic pocket at the receptor as the chloro group in DuP 753 (68) and EXP 3174 (69) and the pentafluoro group in DuP 532 (70), respectively. The impetus for its selection came from bioisosteric considerations based on hydrophobic and electronic substituent constants. An extensive study of the structure-activity relationships revealed several highly potent AII receptor antagonists. An acyl substitution at the 2-position of the pyrrole ring improved activity, most notably in the in vivo rat model. In addition, the 2-substituted pyrrole compounds improved chemical stability toward extremely facile decarboxylation reaction associated with unsubstituted pyrrole analogues, thus facilitating development of these agents. The IC50's of 18, 20, and 42 (< 1 nM) were better than the reference compounds 69 and 70, respectively. These compounds were selective AII antagonists that compete at the AT1 receptor and showed no affinity at the AT2 receptor at concentrations up to 10 microM. Upon intravenous administration in a normotensive rat model, compound 18 inhibited the AII-induced responses with ED50 of 6 micrograms/kg per min. In a renal hypertensive rat model, the antihypertensive potency of compound 18, at a dose of 10 mg/kg, was very similar to those 68 and 69, respectively. Compound 18 demonstrated a dose-related (3-30 mg/kg) decrease in blood pressure that was sustained for greater than 24 h. On the basis of its profile, compound 18, designated as CI-996, has been selected for in-depth studies. The design, synthesis, in vitro, and in vivo structure-activity relationships are described.

A synthesis of 6-amino-7-cyclohexyl-3,5-heptanediol 1 (CDH) and related amino 1,3-diols involving a nucleophilic ring opening of N-acyl activated lactams is described. Stereochemical proof of the 1,3-diol moiety is also presented.

Five renin inhibitors were cocrystallized with endothiapepsin, a fungal enzyme homologous to renin. Crystal structures of inhibitor-bound complexes have provided invaluable insight regarding the three-dimensional structure of the aspartic proteinase family of enzymes, as well as the steric and polar interactions that occur between the proteins and the bound ligands. Beyond this, subtleties of binding have been revealed, including multiple subsite binding modes and subsite interdependencies. This information has been applied in the design of novel potent renin inhibitors and in the understanding of structure-activity relationships and enzyme selectivities.

A series of renin inhibitors containing ester side chains at the P2 subsite are potent inhibitors of primate renin. Derivatives containing the diol isostere (ACDMH) at P1-P1' were the most potent inhibitors. Moderate selectivity for renin was observed relative to the closely related aspartic proteinase cathepsin D. The prototype compound, 4 (PD 132002), inhibited pepsin only weakly. In both high-renin normotensive and high-renin renal hypertensive monkeys, 4 produced substantial reductions in blood pressure after oral administration of 30 mg/kg. The maximum drop in blood pressure observed (24 +/- 4 mmHg) in the renal hypertensive monkey model was comparable to the drop produced by an intravenous infusion of saralasin at a maximally effective dose. Both the magnitude and duration of the oral antihypertensive effect of 4 is greater than that produced by enalkiren, CGP-38560, or CP-80794 by direct comparison in the same hypertensive monkey model. The malonate ester derivatives were prepared as ca. 65:35 mixtures of epimers. The kinetics of epimerization of 4 were investigated in detail, and it was shown to equilibrate rapidly at physiological pH (t1/2 less than 2 min). Fractional crystallization was employed to obtain the individual diastereomers in greater than 98% purity, which were indistinguishable in terms of their activity in vitro or in vivo, presumably due to rapid epimerization under the testing conditions.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

Statine (STA, 8) and its cyclohexyl analog (ACHPA, 9) are obtained by a stereospecific synthesis via tetramic acid chemistry. Amides of STA and ACHPA, useful for the synthesis of antihyperten-sive renin inhibitors, are prepared directly from the intermediate activated lactams 7 by nucleophilic ring opening with amines.

The mass spectral fragmentation of a series of 10 mitosene analogs is described. Major pathways arise through decomposition of the substituents in the 1 and 10 positions and are unaffected by the substituent in the 7 position. The base peak in the spectrum, in most cases, is represented by the basic mitosene ring. The patterns are general for this series of compounds and may have application in elucidating the structure of the DNA alkylation sites involved in reactions with mitosenes or natural mitomycins.

A series of 1-substituted mitosene analogues of the mitomycin antitumor antibiotics was prepared by total synthesis and screened for activity against P388 leukemia in mice. In general, analogues with moderately good leaving groups (mostly esters) at the 1 position were active, whereas analogues without such substituents were inactive or barely active. These results lend support to the idea that mitosenes with leaving groups at position 1 are capable of bifunctional alkylation of DNA in a manner similar to that of mitomycin C. The most active mitosenes were equal in potency (minimum effective dose) to a corresponding aziridinomitosene, but they were less effective in prolonging life span.