title: Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists.
abstract: The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA. Electronic address: shan@arenapharm.com.
authors.forename: Sangdon
authors.initials: S
authors.lastname: Han
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Lars
authors.initials: L
authors.lastname: Thoresen
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Xiuwen
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Sanju
authors.initials: S
authors.lastname: Narayanan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Jae-Kyu
authors.initials: JK
authors.lastname: Jung
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Strah-Pleynet
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Decaire
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Karoline
authors.initials: K
authors.lastname: Choi
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Yue
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Graeme
authors.initials: G
authors.lastname: Semple
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Jayant
authors.initials: J
authors.lastname: Thatte
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Solomon
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Lixia
authors.initials: L
authors.lastname: Fu
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Whelan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Hussien
authors.initials: H
authors.lastname: Al-Shamma
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Gatlin
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Ruoping
authors.initials: R
authors.lastname: Chen
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Huong
authors.initials: H
authors.lastname: Dang
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Pride
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Ibragim
authors.initials: I
authors.lastname: Gaidarov
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Unett
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Behan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Abu
authors.initials: A
authors.lastname: Sadeque
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Khawja A
authors.initials: KA
authors.lastname: Usmani
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Chuan
authors.initials: C
authors.lastname: Chen
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Edwards
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA 92121, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jones
mesh_terms: D000284:Administration, Oral; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy* / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018712:Analgesics, Non-Narcotic; D006575:Heterocyclic Compounds, 3-Ring; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2
keywords: CB2 agonist; Cannabinoid 2 receptor; Pain