1000052-75-4

Upstream product

• 1000046-86-5 4-(2-chlorophenyl)-2,2-dimethylpiperazin-2-one 
• 1000052-72-1 (3R,5S)-3-ethyl-5-{(2S)-1-[(2-nitrophenyl)sulfonyl]aziridin-2-yl}dihydrofuran-2(3H)-one 
• 1000052-56-1 (2R,4E)-6-(benzyloxy)-2-ethylhex-4-enoic acid 
• 1000052-53-8 (4S)-4-benzyl-3-[(2R,4E)-6-(benzyloxy)-2-ethylhex-4-enoyl]-1,3-oxazolidin-2-one 
• 1000147-33-0 (3R,5S)-5-[(1S)-1-amino-2-hydroxyethyl]-3-ethyldihydrofuran-2(3H)-one 
• 1000052-60-7 (3R,5S)-5-[(1R)-2-(benzyloxy)-1-hydroxyethyl]-3-ethyldihydrofuran-2(3H)-one 
• 1000052-62-9 (1R)-2-(benzyloxy)-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl methanesulfonate 
• 1000052-64-1 (3R,5S)-5-[(1S)-1-azido-2-(benzyloxy)ethyl]-3-ethyldihydrofuran-2(3H)-one 
• 1000052-67-4 N-{(1S)-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]-2-hydroxyethyl}-2-nitrobenzenesulfonamide 

Downstream Products

• 1000052-80-1 4-{(2S)-2-amino-2-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}-1-(2-chlorophenyl)-5,5-dimethylpiperazin-2-one 
• 1000052-78-7 tert-butyl {(1S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamate 
• 1436429-24-1 C₂₇H₄₃ClN₄O₄ 
• 1000052-99-2 (2R,4S,5S)-5-amino-6-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-2-ethyl-N-(4-fluorophenyl)-4-hydroxyhexanamide fumarate 
• 1436430-28-2 tert-butyl (4S,5S)-4-{[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]methyl}-5-[(2R)-2-(methoxycarbonyl)butyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate 
• 1000052-82-3 {(1S,2S,4R)-4-(2,2-dimethylpropylcarbamoyl)-1-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-ylmethyl]-2-hydroxyhexyl}carbamic acid t-butyl ester 

Relevant academic research and scientific papers

Lead optimization of 5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)- 4-hydroxyhexanamides to reduce a cardiac safety issue: Discovery of DS-8108b, an orally active renin inhibitor

With the aim to address an undesired cardiac issue observed with our related compound in the recently disclosed novel series of renin inhibitors, further chemical modifications of this series were performed. Extensive structure-activity relationships studies as well as in vivo cardiac studies using the electrophysiology rat model led to the discovery of clinical candidate trans-adamantan-1-ol analogue 56 (DS-8108b) as a potent renin inhibitor with reduced potential cardiac risk. Oral administration of single doses of 3 and 10 mg/kg of 56 in cynomolgus monkeys pre-treated with furosemide led to significant reduction of mean arterial blood pressure for more than 12 h.

Discovery of DS-8108b, a novel orally bioavailable renin inhibitor

A novel orally bioavailable renin inhibitor, DS-8108b (5), showing potent renin inhibitory activity and excellent in vivo efficacy is described. We report herein the synthesis and pharmacological effects of 5 including renin inhibitory activity in vitro, suppressive effects of ex vivo plasma renin activity (PRA) in cynomolgus monkey, pharmacokinetic data, and blood pressure-lowering effects in an animal model. Compound 5 demonstrated inhibitory activities toward human renin (IC50 = 0.9 nM) and human and monkey PRA (IC50 = 1.9 and 6.3 nM, respectively). Oral administration of single doses of 3 and 10 mg/kg of 5 in cynomolgus monkey on pretreatment with furosemide led to dose-dependent significant reductions in ex vivo PRA and sustained lowering of mean arterial blood pressure for more than 12 h.

CYCLIC AMINE COMPOUND

The present invention provides an excellent antihypertensive medicament. The medicament of the present invention comprises a compound having the general formula (I) and the like: [wherein R1: H, substitutable alkyl, substitutable alkenyl, substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; R2: H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R3, R4; H, substitutable alkyl, substitutable alkenyl, substitutable cycloalkyl or the like; R5, R6: H, substitutable alkyl, substitutable cycloalkyl, substitutable alkoxy or the like; R7, R8: H, substitutable alkyl, substitutable cycloalkyl or the like; X: the formula (II) or the like; A: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like; Y: a single bond, substitutable alkylene, substitutable alkenylene, -(CH2)a-X1-(CH2)b- (X1: the formula -NH-, -O- or the like; a, b: 0-5) or the like; B: substitutable cyclic hydrocarbon, substitutable heterocyclyl or the like].