2. Academic Validation
  3. The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors

The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors

  • Bioorg Med Chem Lett. 2016 Jul 1;26(13):3109-3114. doi: 10.1016/j.bmcl.2016.05.001.
John M Keith 1,  Mark S Tichenor 2,  Richard L Apodaca 2,  Wei Xiao 2,  William M Jones 2,  Mark Seierstad 2,  Joan M Pierce 2,  James A Palmer 2,  Michael Webb 2,  Mark J Karbarz 2,  Brian P Scott 2,  Sandy J Wilson 2,  Michelle L Wennerholm 2,  Michele Rizzolio 2,  Raymond Rynberg 2,  Sandra R Chaplan 2,  J Guy Breitenbucher 2
Affiliations

Affiliations

  • 1 Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: jkeith@its.jnj.com.
  • 2 Janssen Pharmaceutical Companies of Johnson & Johnson, L.L.C. 3210 Merryfield Row, San Diego, CA 92121, United States.
PMID: 27189675 DOI: 10.1016/j.bmcl.2016.05.001
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.

Keywords

BBB; Blood brain barrier; Covalent inhibition; FAAH; Heteroaryl urea; Rat PK; Target engagement.

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