Novel low molecular renin inhibitors which show good oral blood pressure lowering effects in marmosets

Bioorganic and Medicinal Chemistry Letters

Volumn 7, Issue 14, 1997, Pages 1863-1868

  Yamada, Yasuki ^a   Ando, Koji ^a   Komiyama, Kazuya ^a   Shibata, Saizo ^a   Nakamura, Ikuro ^b   Hayashi, Yoshiharu ^b   Ikegami, Kiyoteru ^b   Uchida, Itsuo ^a  

^a JAPAN TOBACCO INC   (Japan)

^b Research Laboratories   (Japan)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIHYPERTENSIVE AGENT; CATHEPSIN D; DIPEPTIDYL CARBOXYPEPTIDASE; JTP 2724; JTP 3072; JTP 4129; PEPSIN A; RENIN INHIBITOR; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; BLOOD PRESSURE; CONTROLLED STUDY; DOG; DRUG ACTIVITY; DRUG SYNTHESIS; ENANTIOMER; ENZYME INHIBITION; ENZYME SPECIFICITY; HUMAN; HUMAN TISSUE; IN VITRO STUDY; MARMOSET; MONKEY; NONHUMAN; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; ORAL DRUG ADMINISTRATION; PLASMA RENIN ACTIVITY; STEREOCHEMISTRY; STRUCTURE ACTIVITY RELATION;

EID: 0030799610     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(97)00323-5     Document Type: Article

References (14)

1. a) For review, see: Ocain, T. D.; Abou-Gharbia, M. Drugs Fut. 1991, 16, 37.
2. b) Recently, some nonpeptide renin inhibitors have been reported. For example: Boyd, S. A.; Fung, A. K. L.; Baker, W. R.; Mantei, R. A.; Stein, H. H.; Cohen, J.; Barlow, J. L.; Klinghofer, V.; Wessale, J. L.; Verburg, K. M.; Polakowski, J. S.; Adler, A. L.; Calzadilla, S. V.; Kover, P.; Yao, Z.; Hutchins, C. W.; Denissen, J. F.; Grabowski, B. A.; Cepa, S.; Hoffman, D. J.; Garren, K. W.; Kleinen, H. D. J. Med. Chem. 1994, 37, 2991.
3. a) Shibata, S.; Yamada, Y.; Ikemoto, Y.; Tada, H.; Shirakawa, E.; Ando, K.; Tsuji, H.; Uchida, I.; Nakamura, I.; Hayashi, Y.; Inui, J.; Ikegami, K. The 111th Anual Meeting of the Pharmaceutical Society of Japan. 1991, Abstract, 2, P 201.
4. b) Shibata, S.; Yamada, Y.; Tada, H.; Shirakawa, E.; Ando, K.; Kato, S.; Uchida, I. The 111th Anual Meeting of the Pharmaceutical Society of Japan. 1991, Abstract, 2, P 90.
5. Yamada, Y; Ando, K.; Ikemoto, Y.; Tada, H.; Shirakawa, E.; Shibata, S.; Nakamura, I.; Hayashi, Y.; Ikegami, K.; Uchida, I., submitted for publication in Chem. Pharm. Bull.
6. Renin inhibitors containing 1,2,3,4-tetrahydropyrrolo[3,4-b]indol-3-one or 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one have been reported.: Kempf, D. J.; Condon, S. L. J. Org. Chem. 1990, 55, 1390.
7. a) Synthetic procedure of compound 6 : To a stirred solution of indole-2-carboxylic acid (140 mg, 0.867 mmol) in DMF (3 ml) was successively added HOBT (138 mg, 1.024 mmol) and DCC (179 mg, 0.867 mmol) at 0 °C. After being stirred for 2 h at 0 °C, a solution of compound 3 (300 mg, 0.788 mmol) in DMF (3 ml) was added to the mixture. The mixture was warmed to room temperature and stirred for 13 h. After filtration of the mixture, the filtrate was evaporated in vacuo. To the residue was added a combined solution of MeOH, water, and AcOH (94 : 3 : 3), and the mixture was heated at 60 °C for 30 min. After evaporation in vacuo, the residue was dissolved in CHCl3, and the organic solution was washed twice with sat. NaHCO3, dried over MgSO4, then evaporated in vacuo. The residue was purified by silica gel chromatography with CHCl3 and MeOH (20 : 1) as an eluent to give 6 (237 mg, 57 %) as a colorless amorphous solid. Other compounds listed in Table 1 were prepared by essentially the same methods.
8. 1H-NMR and MS.
9. In vitro renin inhibitory assay : The renin inhibitory effect of compounds was evaluated for plasma renin activity (PRA) of human plasma. The assay was consisted of 200 μ 1 of EDTA-plasma, 20 μ 1 of citrate buffer, 10 μ 1 of phenylmethylsulfonyl fluoride, and 10 μ 1 of various concentrations of compound in DMSO. The reaction mixture was incubated at 37 °C for 60 min. After incubation, the PRA was estimated by measurement of the produced angiotensin I, which was quantified by radioimmunoassay using a commercial kit (RENIN RIABEAD, Dinabot Ltd., Japan). The percentage of inhibition was calculated at each concentration of point, and the concentration of renin inhibitors that inhibited PRA by 50 % (IC50) was estimated. The species specificity of renin inhibitors was evaluated by comparison of the renin inhibitory effect on human, cynomolgus monkey, marmoset, dog, and rat plasmas.
10. a) Karanewsky, D. S.; Badia, M. C.; Cushman, D. W.; DeForrest, J. M.; Dejneka, T.; Lee, V. G.; Loots, M. J.; Petrillo, E. W. J. Med. Chem., 1990, 33, 1459.
11. b) Klutchko, S.; Blankley, C. J.; Fleming, R. W.; Hinkley, J. M.; Werner, A. E.; Nordin, I.; Holmes, A.; Hoefle, M. L.; Cohen, D. M.; Essenburg, A. D.; Kaplan, H. R. J. Med. Chem. 1986, 29, 1953.
12. The reported pKa values of indole-NH and benzimidazole-NH are 16.97 and 13.2, respectively.: Gilchlist, T. L. "Heterocyclic Chemistry" 1985, Pitman Publishing, London.
13. In vivo marmoset model : Conscious marmosets raised on a low salt diet (containing 0.02 % salt, 1/10 of the normal diet) for a week were orally administered with the inhibitor (10 mg/kg) dissolved in 0.1 M citric acid, at the ratio of 2 ml/kg. The blood pressure was measured with the lapse of time before and after the administration by the tail-cuff method.
14. Enzyme specificity : The enzyme specificity of renin inhibitors was evaluated by comparison of the inhibitory effect on renin, pepsin, cathepsin D, and ACE. Porcine pepsin (Sigma Chemical Co., USA) or bovine cathepsin D (Sigma Chemical Co.) was incubated at 37 °C for 10 or 30 min with bovine hemoglobin (Sigma Chemical Co.) as a substrate in the presence and absence of inhibitor. After incubation, proteins were precipitated with trichloroacetic acid and absorbance of the supernatant was measured at the wavelength of 280 nm. Inhibition of human serum ACE was estimated using a commercial assay kit (ACE color, Fujirebio Inc., Japan). Human serum was incubated at 37 °C for 20 min with the substrate mixture of p-hydroxybenzoylglycyl-L-histidyl-L-leucine and hippuricase in the presence and absence of inhibitor. The reaction mixture was incubated with NaIO4 and absorbance of solution was measured at the wavelength of 505 nm.