title: The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors.
abstract: The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4:1 to as low as 0.02:1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (Vd) obtained from pharmacokinetic (PK) experiments as very high Vds did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement.
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: jkeith@its.jnj.com.
authors.forename: John M
authors.initials: JM
authors.lastname: Keith
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Tichenor
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Apodaca
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: William M
authors.initials: WM
authors.lastname: Jones
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Seierstad
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Joan M
authors.initials: JM
authors.lastname: Pierce
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: James A
authors.initials: JA
authors.lastname: Palmer
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Webb
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Karbarz
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Scott
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Wennerholm
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Rizzolio
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Raymond
authors.initials: R
authors.lastname: Rynberg
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: Sandra R
authors.initials: SR
authors.lastname: Chaplan
authors.affiliation: Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
authors.forename: J Guy
authors.initials: JG
authors.lastname: Breitenbucher
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases
keywords: BBB; Blood brain barrier; Covalent inhibition; FAAH; Heteroaryl urea; Rat PK; Target engagement