title: Lead optimization toward proof-of-concept tools for Huntington's disease within a 4-(1H-pyrazol-4-yl)pyrimidine class of pan-JNK inhibitors.
abstract: Through medicinal chemistry lead optimization studies focused on calculated properties and guided by X-ray crystallography and computational modeling, potent pan-JNK inhibitors were identified that showed submicromolar activity in a cellular assay. Using in vitro ADME profiling data, 9t was identified as possessing favorable permeability and a low potential for efflux, but it was rapidly cleared in liver microsomal incubations. In a mouse pharmacokinetics study, compound 9t was brain-penetrant after oral dosing, but exposure was limited by high plasma clearance. Brain exposure at a level expected to support modulation of a pharmacodynamic marker in mouse was achieved when the compound was coadministered with the pan-cytochrome P450 inhibitor 1-aminobenzotriazole.
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: John
authors.initials: J
authors.lastname: Wityak
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Kevin F
authors.initials: KF
authors.lastname: McGee
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Conlon
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Ren Hua
authors.initials: RH
authors.lastname: Song
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Duffy
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Brent
authors.initials: B
authors.lastname: Clayton
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Lynch
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Gwen
authors.initials: G
authors.lastname: Wang
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Emily
authors.initials: E
authors.lastname: Freeman
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: James
authors.initials: J
authors.lastname: Haber
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kitchen
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: David D
authors.initials: DD
authors.lastname: Manning
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Jiffry
authors.initials: J
authors.lastname: Ismail
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Khmelnitsky
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Peter
authors.initials: P
authors.lastname: Michels
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Jeff
authors.initials: J
authors.lastname: Webster
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Macarena
authors.initials: M
authors.lastname: Irigoyen
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Luche
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Monica
authors.initials: M
authors.lastname: Hultman
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Mei
authors.initials: M
authors.lastname: Bai
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: IokTeng D
authors.initials: ID
authors.lastname: Kuok
authors.affiliation: ‡Albany Molecular Research Inc. (AMRI), 26 Corporate Circle, Albany, New York 12212-5098, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Newell
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Marieke
authors.initials: M
authors.lastname: Lamers
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Philip
authors.initials: P
authors.lastname: Leonard
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Dawn
authors.initials: D
authors.lastname: Yates
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Kim
authors.initials: K
authors.lastname: Matthews
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Lynette
authors.initials: L
authors.lastname: Ongeri
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Steve
authors.initials: S
authors.lastname: Clifton
authors.affiliation: §BioFocus Discovery Services, Charles River Laboratories, Chesterford Research Park, Little Chesterford, CB10 1XL, United Kingdom.
authors.forename: Tania
authors.initials: T
authors.lastname: Mead
authors.affiliation: ∥Tandem Laboratories, 2202 Ellis Road, Durham, North Carolina 27703, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Deupree
authors.affiliation: ∥Tandem Laboratories, 2202 Ellis Road, Durham, North Carolina 27703, United States.
authors.forename: Pat
authors.initials: P
authors.lastname: Wheelan
authors.affiliation: ⊥Pharmacokinetics Consultant to CHDI, P.O. Box 64, Holland, New York 14080, United States.
authors.forename: Kathy
authors.initials: K
authors.lastname: Lyons
authors.affiliation: #Evotec, 114 Milton Park, Abingdon, OX14 4SA, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Wilson
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Alex
authors.initials: A
authors.lastname: Kiselyov
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Leticia
authors.initials: L
authors.lastname: Toledo-Sherman
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Muñoz-Sanjuan
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.affiliation: †CHDI Foundation, Inc., 6080 Center Drive, Suite 100, Los Angeles, California 90045, United States.
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D018360:Crystallography, X-Ray; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006207:Half-Life; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy / Q000378:metabolism; D020128:Inhibitory Concentration 50; D061985:Madin Darby Canine Kidney Cells / Q000187:drug effects; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D048057:Mitogen-Activated Protein Kinase 10 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011720:Pyrazoles / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D048057:Mitogen-Activated Protein Kinase 10; C030986:pyrimidine