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A dihydroxyethylene isostere, (2S, 3R, 4S)-4-amino-5-cyclohexyl-1-morpholino-2, 3-pentanediol (ACMP, 1), which is a component of non-peptidic, orally active, low-molecular-weight renin inhibitors, was synthesized stereospecifically starting from 3-cyclohexyl-L-alanine via iodo-cyclocarbamation as the key reaction.

The synthesis and structure-activity relationships of transition-state renin inhibitors containing the homostatine analogues at the scissile bond are described. These inhibitors incorporate the amino acid side chains corresponding to positions 7-12 (P4-P2') of angiotensinogen. Ethyl, 2-hydroxyethyl and 3-hydroxypropyl groups at position 2 of the homostatine analogues (P1') are more effective for increasing potency than the isopropyl group. A combination of residues at P1, P3 and P4 is important for potency and this result suggests that S1, S3 and S4 form a huge hydrophobic core together in renin.

A homostatine analogue, (2RS,4S,5S)N-isobutyl-5-amino-2-ethyl-4-hydroxy-7-methyloctanamide, was synthesized starting from natural statine. The modified Horner–Wadsworth–Emmons reaction of (4S,5R)-3-benzyloxycarbonyl-5-formyl-4-isobutyl-2,2-dimethyloxazolidine is a key reaction for the synthesis of a homostatine analogue. Stereoselective and stereospecific syntheses of a N-terminal precursor, N-[(2R)-3-hydroxy-2-(1-naphthylmethyl)propionyl]-L-norleucine t-butyl ester and a total synthesis of a highly active renin inhibitor, (2RS,4S,5S)-N-isobutyl-5-[[N-[(2S)-2-(1-naphthylmethyl)-3-(2-pyrimidinylsulfonyl)propionyl]-L-norleucyl]amino]-2-ethyl-4-hydroxy-7-methyloctanamide are described.

We describe an efficient synthesis of highly active renin inhibitors containing a sulfonemethylene isostere at their N-terminals and a hydroxyethylene isostere at their C-terminals. The stereospecific synthesis of N-terminal key intermediate, L-N-[(2R)-2-benzyl(or 1-naphthylmethyl)-3-hydroxypropionyl]norleucine t-butyl ester is described.

(2 S , 3 R , 4 S )-4-[L-N-[(2 S )-3-ethylsulfonyl-2-(1-naphthylmethyl) propionyl]norleucyl]amino-5-cyclohexyl-1-morpholino-2,3-pentanediol(BW-175) was synthesized stereospecifically.

The key intermediates, 2-substituted-3-hydroxypropionic acids 1 , of the potent renin inhibitors were synthesized enantioselectively starting from 2-substituted-l,3-propanediols via chemo-enzymatic reaction.

A transition-state analogue of a renin inhibitor at the scissile site, a dihydroxyethylene isostere of cyclohexylalanine amide, (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol(ACMP), was synthesized from 1,2:5,6-di-O-isopropylidene-α-D-allofuranose stereospecifically.

A dihydroxyethylene isostere, (2S, 3R, 4S)-4-amino-5-cyclohexyl-1-morpholino-2, 3-pentanediol (ACMP, 1), which is a component of non-peptidic, orally active, low-molecular-weight renin inhibitors, was synthesized stereospecifically starting from 3-cyclohexyl-L-alanine via iodo-cyclocarbamation as the key reaction.

A dihydroxyethylene isostere, (2S, 3R, 4S)-4-amino-5-cyclohexyl-1-morpholino-2, 3-pentanediol, which is a component of non-peptidic, orally active, low-molecular-weight renin inhibitors, was synthesized stereospecifically starting from prochiral divinylcarbinol via the Sharpless epoxidation.

The design, synthesis and structure-activity relationships of transition-state inhibitors containing the dihydroxyethylene isostere at the scissile site are described. The compounds with (2S,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol at the P1-P1 site are potent renin inhibitors. (2S,3R,4S)-4-[N-[(2S)-3-Ethylsulfonyl-2-(1-naphthylmethyl)propiony l]-L- norleucyl]amino-5-cyclohexyl-1-morpholino-2,3-pentanediol (2) (BW-175), which is the most potent inhibitor (IC50: 3.3 nM against human renin) in this series, poorly inhibits cathepsin D (IC50: 26000 nM) and pepsin (IC50: > 100000 nM), and thus it is specific for renin. Compound 2 contains only one amino acid and showed an oral bioavailability of 2.8% at 10 mg/kg and 9.7% at 30 mg/kg in rats. The interaction between renin and inhibitor 2 is discussed on the basis of molecular modeling studies.

The synthesis and structure-activity relationships of N-terminus modified renin inhibitors containing the homostatine analogue, (2RS, 4S, 5S)-5-amino-2-ethyl-4-hydroxy-7-methyloctanoic acid, are described. The compounds having a 3-alkyl (or aryl)sulfonylpropionyl residue at the N-terminus are found to be potent inhibitors which contain two amino acids. (2RS, 4S, 5S)-N-Isobutyl-5-[N-[(2S)-3-ethylsulfonyl-2-(1-naphthylmethyl)propionyl]-L-norleucyl]-amino-2-ethyl-4-hydroxy-7-methyloctanamie (20) has an IC50 of 0.5 nM against human plasma renin and the oral bioavailability of 20 is 0.73% in rats. Interaction between renin and the N-terminus of 1 and 20 is discussed in molecular modeling studies.

A homostatine analogue, (2RS,4S,5S)N-isobutyl-5-amino-2-ethyl-4-hydroxy-7-methyloctanamide, was synthesized starting from natural statine. The modified Horner–Wadsworth–Emmons reaction of (4S,5R)-3-benzyloxycarbonyl-5-formyl-4-isobutyl-2,2-dimethyloxazolidine is a key reaction for the synthesis of a homostatine analogue. Stereoselective and stereospecific syntheses of a N-terminal precursor, N-[(2R)-3-hydroxy-2-(1-naphthylmethyl)propionyl]-L-norleucine t-butyl ester and a total synthesis of a highly active renin inhibitor, (2RS,4S,5S)-N-isobutyl-5-[[N-[(2S)-2-(1-naphthylmethyl)-3-(2-pyrimidinylsulfonyl)propionyl]-L-norleucyl]amino]-2-ethyl-4-hydroxy-7-methyloctanamide are described.

The 1,3-diols (I) are enantioselectively monoesterified in the presence of lipase P from Pseudomonas fluorescens to yields the chiral acetates (+)-(III).

Les composes du titre substitues en 2 ou 4 sont obtenus par cyclisation par POCl 3 d'acylamino-1' alkyl-2 dihydro-3,4 methyl-6 pyrimidones-4 suivie de reactions nucleophiles des chloro-2- et chloro-4 imidazo [1,5-a] pyrimidines formees

Treatment of the β-D-ribofuranosyl cyanide 5 with sodium methoxide, followed by reaction with diketene, gave the spiro 1, 3-oxazine 6, which underwent the ring transformation with ammonia and phenylhydrazine to give the protected pyrimidine (8) and 1, 2, 4-triazole (13) C-nucleosides, respectively. Deprotection of 8 with 90% trifluoroacetic acid gave the pyrimidine C-nucleoside 9. Passage of hydrogen chloride gas over a solution of the cyanide 1 and benzyl hydrosulfide gave the fully protected ribofuranosylthioformimidate 15. Treatment of 15 with triethylamine, followed by reaction with diketene gave the dihydrofuran derivative 16. Compound 16, on treatment with ammonia, hydroxylamine, and phenylhydrazine, was transformed into the corresponding furan derivatives 17-19.

Treatment of the β-D-ribofuranosyl cyanide 5 with sodium methoxide, followed by reaction with diketene, gave the spiro 1, 3-oxazine 6, which underwent the ring transformation with ammonia and phenylhydrazine to give the protected pyrimidine (8) and 1, 2, 4-triazole (13) C-nucleosides, respectively. Deprotection of 8 with 90% trifluoroacetic acid gave the pyrimidine C-nucleoside 9. Passage of hydrogen chloride gas over a solution of the cyanide 1 and benzyl hydrosulfide gave the fully protected ribofuranosylthioformimidate 15. Treatment of 15 with triethylamine, followed by reaction with diketene gave the dihydrofuran derivative 16. Compound 16, on treatment with ammonia, hydroxylamine, and phenylhydrazine, was transformed into the corresponding furan derivatives 17-19.