Potent, selective and orally bioavailable leucine-rich repeat kinase 2 (LRRK2) inhibitors.
Familial Parkinson's disease cases have recently been associated with the leucine rich repeat kinase 2 (LRRK2) gene. It has been hypothesized that inhibition of the LRRK2 protein may have the potential to alter disease pathogenesis. A dihydrobenzothiophene series of potent, selective, orally bioavailable LRRK2 inhibitors were identified from a high-throughput screen of the internal Merck sample collection. Initial SAR studies around the core established the series as a tractable small molecule lead series of LRRK2 inhibitors for potential treatment of Parkinson's disease. It was also found that incorporation of a lactam into the core drastically improved the CNS and DMPK properties of these small molecules.
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States. Electronic address: thomas_greshock@merck.com.
Thomas J
TJ
Greshock
Department of Chemistry Modeling and Informatics, Merck Research Laboratories, West Point, PA 19486, United States. Electronic address: john_sanders@merck.com.
John M
JM
Sanders
Department of Neuroscience Research, Merck Research Laboratories, West Point, PA 19486, United States.
Robert E
RE
Drolet
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Hemaka A
HA
Rajapakse
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Ronald K
RK
Chang
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Boyoung
B
Kim
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Vanessa L
VL
Rada
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Heather E
HE
Tiscia
Department of Structural Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Hua
H
Su
Department of In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
Ming-Tain
MT
Lai
Department of In Vitro Pharmacology, Merck Research Laboratories, West Point, PA 19486, United States.
Sylvie M
SM
Sur
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, United States.
Rosa I
RI
Sanchez
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
Mark T
MT
Bilodeau
Department of Neuroscience Research, Merck Research Laboratories, West Point, PA 19486, United States.
John J
JJ
Renger
Department of Neuroscience Research, Merck Research Laboratories, West Point, PA 19486, United States.
Jonathan T
JT
Kern
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, United States.
John A
JA
McCauley
D000284:Administration, Oral; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D047428:Protein Kinase Inhibitors; D013876:Thiophenes; C088015:benzothiophene; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
CNS; Kinase; LRRK2; Leucine rich repeat kinase; Parkinson’s disease