Iminopyrimidinones: a novel pharmacophore for the development of orally active renin inhibitors.
The development of renin inhibitors with favorable oral pharmacokinetic profiles has been a longstanding challenge for the pharmaceutical industry. As part of our work to identify inhibitors of BACE1, we have previously developed iminopyrimidinones as a novel pharmacophore for aspartyl protease inhibition. In this letter we describe how we modified substitution around this pharmacophore to develop a potent, selective and orally active renin inhibitor.
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: brian.mckittrick@merck.com.
Brian A
BA
McKittrick
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. Electronic address: john.caldwell@merck.com.
John P
JP
Caldwell
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Thomas
T
Bara
Cardiovascular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
George
G
Boykow
Cardiovascular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Madhu
M
Chintala
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
John
J
Clader
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Michael
M
Czarniecki
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Brandy
B
Courneya
Cardiovascular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Ruth
R
Duffy
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Linda
L
Fleming
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Rachel
R
Giessert
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
William J
WJ
Greenlee
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Charles
C
Heap
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Liwu
L
Hong
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Ying
Y
Huang
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Ulrich
U
Iserloh
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Hubert
H
Josien
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Tanweer
T
Khan
Pharmacokinetics Pharmacodynamics and Metabolism, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Walter
W
Korfmacher
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Xian
X
Liang
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Robert
R
Mazzola
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Soumya
S
Mitra
Cardiovascular Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Kristina
K
Moore
Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Peter
P
Orth
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Murali
M
Rajagopalan
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Sudipta
S
Roy
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Samuel
S
Sakwa
Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Corey
C
Strickland
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Henry
H
Vaccaro
Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Johannes
J
Voigt
Structural Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Hongwu
H
Wang
Discovery Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Jesse
J
Wong
Biochemistry and Biophysics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States.
Rumin
R
Zhang
Medicinal Chemistry Department, Albany Molecular Research, Inc., 26 Corporate Circle, Albany, NY 12203, United States.
Andrew
A
Zych
D000284:Administration, Oral; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D007097:Imines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D012083:Renin / Q000378:metabolism; D013329:Structure-Activity Relationship; D000092502:Renin Inhibitors
D004791:Enzyme Inhibitors; D007097:Imines; D011744:Pyrimidinones; D012083:Renin; D000092502:Renin Inhibitors
BACE1; Enzyme inhibitors; Hypertension; Renin inhibitors; Structure-based drug design