Optimisation of a novel series of selective CNS penetrant CB(2) agonists

Christine Watson; Dafydd R Owen; Denise Harding; Kana Kon-I; Mark L Lewis; Helen J Mason; Miyako Matsumizu; Takasuke Mukaiyama; Margarita Rodriguez-Lens; Akiko Shima; Mifune Takeuchi; Isabelle Tran; Tim Young

doi:10.1016/j.bmcl.2011.05.063

Optimisation of a novel series of selective CNS penetrant CB(2) agonists

Bioorg Med Chem Lett. 2011 Jul 15;21(14):4284-7. doi: 10.1016/j.bmcl.2011.05.063. Epub 2011 May 25.

Authors

Christine Watson¹, Dafydd R Owen, Denise Harding, Kana Kon-I, Mark L Lewis, Helen J Mason, Miyako Matsumizu, Takasuke Mukaiyama, Margarita Rodriguez-Lens, Akiko Shima, Mifune Takeuchi, Isabelle Tran, Tim Young

Affiliation

¹ Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom. christine.watson100@gmail.com

PMID: 21669533
DOI: 10.1016/j.bmcl.2011.05.063

Abstract

A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.

MeSH terms

Analgesics / chemical synthesis
Analgesics / chemistry*
Analgesics / pharmacokinetics
Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacokinetics
Central Nervous System / metabolism*
Microsomes, Liver / metabolism
Rats
Receptor, Cannabinoid, CB1 / agonists
Receptor, Cannabinoid, CB1 / metabolism
Receptor, Cannabinoid, CB2 / agonists*
Receptor, Cannabinoid, CB2 / metabolism
Structure-Activity Relationship

Substances

Analgesics
Benzimidazoles
Receptor, Cannabinoid, CB1
Receptor, Cannabinoid, CB2
benzimidazole