Synthesis and optimization of novel (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as orally active renin inhibitors

被引：9

作者：

Mori, Yutaka ^{[1
]}

Ogawa, Yasuyuki ^{[2
]}

Mochizuki, Akiyoshi ^{[3
]}

Nakamura, Yuji ^{[3
]}

Fujimoto, Teppei ^{[3
]}

Sugita, Chie ^{[3
]}

Miyazaki, Shojiro ^{[3
]}

Tamaki, Kazuhiko ^{[3
]}

Nagayama, Takahiro ^{[4
]}

Nagai, Yoko ^{[5
]}

Inoue, Shin-ichi ^{[5
]}

Chiba, Katsuyoshi ^{[6
]}

Nishi, Takahide ^{[7
]}

机构：

[1] Daiichi Sankyo Co Ltd, New Modal Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[2] Daiichi Sankyo Co Ltd, Venture Sci Labs, Shinagawa Ku, Tokyo 1408710, Japan

[3] Daiichi Sankyo Co Ltd, Med Chem Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[4] Daiichi Sankyo Co Ltd, Cardiovasc Metabol Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[5] Daiichi Sankyo Co Ltd, Drug Metab & Pharmacokinet Res Labs, Shinagawa Ku, Tokyo 1408710, Japan

[6] Daiichi Sankyo Co Ltd, Med Safety Res Labs, Edogawa Ku, Tokyo 1348630, Japan

[7] Daiichi Sankyo India Pharma Pvt Ltd, Daiichi Sankyo Life Sci Res Ctr India, Gurgaon 122015, Haryana, India

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2013年 / 21卷 / 18期

关键词：

Hypertension; Renin; Piperidine; Ketopiperazine; TRANSGENIC RATS; BLOOD-PRESSURE; DISCOVERY; DESIGN; ALISKIREN; POTENT; MARMOSETS; DS-8108B;

D O I：

10.1016/j.bmc.2013.06.057

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of P-1', P-2' and P-3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys. (C) 2013 Elsevier Ltd. All rights reserved.

引用

页码：5907 / 5922

页数：16

共 50 条

[31] 2-Chloro-N-{5-[(4R,5R,10S)-dehydroabiet-4-yl]-1,3,4-thiadiazol-2-yl}benzamide
Mo, Qijin
Duan, Wengui
Ma, Xianli
Huang, Jianxin
Ma, Zhen
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2011, 67 : O816 - U1796
[32] (S)-3-Chloro-4-(4-ethylpiperazin-1-yl)-5-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy]furan-2(5H)-one
Fu, Jian-Hua
Wang, Zhao-Yang
Yang, Kai
Mao, Chao-Xu
ACTA CRYSTALLOGRAPHICA SECTION E-STRUCTURE REPORTS ONLINE, 2010, 66 : O2022 - U1241
[33] Total synthesis of 4-((3S,5R)-3,5-dihydroxynonadecyl)phenol
Rajendar, Potham
Desikan, Srinivasa
Sridhar, Gattu
Tripuramallu, Bharat Kumar
SYNTHETIC COMMUNICATIONS, 2022, 52 (17) : 1721 - 1726
[34] Stereoselective synthesis of (2R,3S,4S,5R)-trans-3,4-dihydroxy-5-(4-fluorophenoxymethyl)-2-(1-N-hydroxyureidyl-3-butyn-4-yl)tetrahydrofuran and (2R,3S,4S,5R)-trans-5-ethynyl-2(4-fluorophenoxymethyl)-3,4-O-isopropylidene tetrahydrofuran from mannose diacetonide
Sharma, GVM
Punna, S
Hymavathi, L
Reddy, NY
Krishna, PR
Chorghade, MS
Ley, SV
TETRAHEDRON-ASYMMETRY, 2005, 16 (06) : 1135 - 1140
[35] STEREOSPECIFIC ROUTE FOR THE SYNTHESIS OF 1,5-LACTAMS - SYNTHESIS OF (2S,3S,4R,5R)-METHYL-3,4,5-TRIPHENYL-METHYLENOXY-6-OXO-PIPERIDINE-2-CARBOXYLATE
GUNTHA, S
MEREYALA, HB
TETRAHEDRON LETTERS, 1994, 35 (27) : 4869 - 4870
[36] (2S,3S,5R)-5-ALLYL-5-METHOXY-2-(3',4',5'-TRIMETHOXYPHENYL)-3-METHYL-2,3,5,6-TETRAHYDRO-6-OXOBENZOFURAN
TOMITA, K
JEFFREY, GA
SHIONO, R
ACTA CRYSTALLOGRAPHICA SECTION B-STRUCTURAL SCIENCE, 1977, 33 (NOV): : 3576 - 3580
[37] A Concise Synthesis of (-)-(3S, 4S, 5R, 7S)-Dehydroclausenamide
厦门大学学报(自然科学版), 1999, (S1) : 106 - 106
[38] Asymmetric synthesis of a sex pheromone (3S,5R,6S)-3,5-dimethyl-6-isopropyl-3,4,5,6-tetrahydropyran-2-one
Prabhakar, Peddikotla
Rajaram, Singanaboina
Venkateswarlu, Yenamandra
TETRAHEDRON-ASYMMETRY, 2009, 20 (15) : 1806 - 1808
[39] Parallel Synthesis of 1-Substituted 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4-carboxamides
Perdih, Peter
Baskovc, Jernej
Dahmann, Georg
Groselj, Uros
Kocar, Drago
Novak, Ana
Stanovnik, Branko
Svete, Jurij
SYNTHESIS-STUTTGART, 2011, (17): : 2822 - 2832
[40] Stereodivergent synthesis of (2S,3S,4R,5R)- and (2S,3S,4R,5S)-[3,4,5-D3]proline depending on the substituent of the γ-lactam ring
Oba, M
Miyakawa, A
Nishiyama, K
Terauchi, T
Kainosho, M
JOURNAL OF ORGANIC CHEMISTRY, 1999, 64 (25): : 9275 - 9278

← 1 2 3 4 5 →