Structure-based design of a new series of N-(piperidin-3-yl)pyrimidine-5-carboxamides as renin inhibitors.
The action of the aspartyl protease renin is the rate-limiting initial step of the renin-angiotensin-aldosterone system. Therefore, renin is a particularly promising target for blood pressure as well as onset and progression of cardiovascular and renal diseases. New pyrimidine derivatives 5-14 were designed in an attempt to enhance the renin inhibitory activity of compound 3 identified by our previous fragment-based drug design approach. Introduction of a basic amine essential for interaction with the two aspartic acids in the catalytic site and optimization of the S1/S3 binding elements including an induced-fit structural change of Leu114 ('Leu-in' to 'Leu-out') by a rational structure-based drug design approach led to the discovery of N-(piperidin-3-yl)pyrimidine-5-carboxamide 14, a 65,000-fold more potent renin inhibitor than compound 3. Surprisingly, this remarkable enhancement in the inhibitory activity of compound 14 has been achieved by the overall addition of only seven heavy atoms to compound 3. Compound 14 demonstrated excellent selectivity over other aspartyl proteases and moderate oral bioavailability in rats.
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yasuhiro.imaeda@takeda.com.
Yasuhiro
Y
Imaeda
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Michiko
M
Tawada
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Shinkichi
S
Suzuki
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Masaki
M
Tomimoto
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Mitsuyo
M
Kondo
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Naoki
N
Tarui
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Tsukasa
T
Sanada
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Ray
R
Kanagawa
Takeda California, Inc., 10410, Science Center Drive, San Diego, CA 92121, United States.
Gyorgy
G
Snell
Takeda California, Inc., 10410, Science Center Drive, San Diego, CA 92121, United States.
Craig A
CA
Behnke
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Keiji
K
Kubo
Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraoka-Higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan.
Takanobu
T
Kuroita
D000818:Animals; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000097:blood; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D010880:Piperidines; D011480:Protease Inhibitors; D011743:Pyrimidines; D012083:Renin; D000092502:Renin Inhibitors; C000621695:N-(piperidin-3-yl)pyrimidine-5-carboxamide
Crystal structure; N-(Piperidin-3-yl)pyrimidine-5-carboxamide; Renin inhibitor; Structure-based drug design (SBDD)