title: Design and synthesis of aminohydantoins as potent and selective human β-secretase (BACE1) inhibitors with enhanced brain permeability.
abstract: The identification of small molecule aminohydantoins as potent and selective human β-secretase inhibitors is reported. These analogs exhibit good brain permeability (40-70%), low nanomolar potency for BACE1, and demonstrate >100-fold selectivity for the structurally related aspartyl proteases cathepsin D, renin and pepsin. Alkyl and alkoxy groups at the meta-position of the P1 phenyl, which extend toward the S3 region of the enzyme, have contributed to the ligand's reduced affinity for the efflux transporter protein P-gp, and decreased topological polar surface area, thus resulting in enhanced brain permeability. A fluorine substitution at the para-position of the P1 phenyl has contributed to 100-fold decrease of CYP3A4 inhibition and enhancement of compound metabolic stability. The plasma and brain protein binding properties of these new analogs are affected by substitutions at the P1 phenyl moiety. Higher compound protein binding was observed in the brain than in the plasma. Two structurally diverse potent BACE1 inhibitors (84 and 89) reduced 30% plasma Aβ40 in the Tg2576 mice in vivo model at 30 mg/kg p.o..
authors.affiliation: Department of Chemical Sciences, Pfizer, CN 8000, Princeton, NJ 08543-8000, USA. malamas.michael@gmail.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Albert
authors.initials: A
authors.lastname: Robichaud
authors.forename: Jim
authors.initials: J
authors.lastname: Erdei
authors.forename: Dominick
authors.initials: D
authors.lastname: Quagliato
authors.forename: William
authors.initials: W
authors.lastname: Solvibile
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Koi
authors.initials: K
authors.lastname: Morris
authors.forename: Jim
authors.initials: J
authors.lastname: Turner
authors.forename: Erik
authors.initials: E
authors.lastname: Wagner
authors.forename: Kristi
authors.initials: K
authors.lastname: Fan
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Steve
authors.initials: S
authors.lastname: Jacobsen
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhart
authors.forename: David
authors.initials: D
authors.lastname: Riddell
authors.forename: Menelas
authors.initials: M
authors.lastname: Pangalos
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D001921:Brain / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006827:Hydantoins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010539:Permeability
chemical_list: D004791:Enzyme Inhibitors; D006827:Hydantoins; D053829:Amyloid Precursor Protein Secretases