title: 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.
abstract: 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.
authors.affiliation: Lead Discovery & Optimization Research Laboratories I, Daiichi Sankyo Co., Ltd, 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. nakamura.yuji.mf@daiichisankyo.co.jp
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Teppei
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Namiki
authors.forename: Sayaka
authors.initials: S
authors.lastname: Suzuki
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Asano
authors.forename: Chie
authors.initials: C
authors.lastname: Sugita
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Mochizuki
authors.forename: Shojiro
authors.initials: S
authors.lastname: Miyazaki
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tamaki
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagai
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Inoue
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nagayama
authors.forename: Mikio
authors.initials: M
authors.lastname: Kato
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Chiba
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takasuna
authors.forename: Takahide
authors.initials: T
authors.lastname: Nishi
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001145:Arrhythmias, Cardiac / Q000517:prevention & control*; D062186:Arterial Pressure / Q000187:drug effects; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D008252:Macaca fascicularis; D008297:Male; D009924:Organ Culture Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D012083:Renin / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
chemical_list: D000959:Antihypertensive Agents; D010879:Piperazines; D011480:Protease Inhibitors; D012083:Renin; D000092502:Renin Inhibitors