title: Pharmacological characterization of a novel α2C-adrenoceptor agonist N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N'-methylurea (compound A).
abstract: We define the pharmacological and pharmacokinetic profiles of a novel α(2C)-adrenoceptor agonist, compound A [N-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl]-N-ethyl-N'-methylurea]. This compound has high affinity (K(i)) for the human α(2C)-adrenoceptor (K(i) = 12 nM), and 190- to 260-fold selectivity over the α(2A)- and α(2B)-adrenoceptor subtypes. In cell-based functional assays, compound A produced good agonist (EC(50) = 166 nM) and efficacy (E(max) = 64%) responses at the α(2C)-adrenoceptor, much lower potency and efficacy at the α(2A)-adrenoceptor (EC(50) = 1525 nM; E(max) = 8%) and α(2B)-adrenoceptor (EC(50) = 5814 nM; E(max) = 21%) subtypes, and low or no affinity and functional activity at the α(1A)-, α(1B)-, and α(1D)-adrenoceptor subtypes. In the human saphenous vein postjunctional α(2C)-adrenoceptor bioassay, compound A functions as a potent agonist (pD(2) = 6.3). In a real-time contraction bioassay of pig nasal mucosa, compound A preferentially constricted the veins (EC(50) = 108 nM), and the magnitude of arteriolar contraction reached only 50% of the maximum venular responses. Compound A exhibited no effect on locomotor activity, sedation, and body temperature in mice (up to 100 mg/kg) and did not cause hypertension and mydriasis (30 mg/kg) in conscious rats. Compound A is orally bioavailable (24%) with good plasma exposure. This compound is a substrate for the efflux P-glycoprotein transporter, resulting in very low central nervous system (CNS) penetration. In summary, compound A is a highly selective, orally active, and non-CNS-penetrating α(2C)-adrenoceptor agonist with desirable in vitro and in vivo pharmacological properties suitable for the treatment of nasal congestion.
authors.affiliation: In Vivo Pharmacology, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. michel.corboz@merck.com
authors.forename: Michel R
authors.initials: MR
authors.lastname: Corboz
authors.forename: Maria A
authors.initials: MA
authors.lastname: Rivelli
authors.forename: Kevin D
authors.initials: KD
authors.lastname: McCormick
authors.forename: Yuntao
authors.initials: Y
authors.lastname: Wan
authors.forename: Himanshu
authors.initials: H
authors.lastname: Shah
authors.forename: Shelby
authors.initials: S
authors.lastname: Umland
authors.forename: Gisela
authors.initials: G
authors.lastname: Lieber
authors.forename: Yanlin
authors.initials: Y
authors.lastname: Jia
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: Cynthia
authors.initials: C
authors.lastname: Morgan
authors.forename: Geoffrey B
authors.initials: GB
authors.lastname: Varty
authors.forename: Jie
authors.initials: J
authors.lastname: Wu
authors.forename: Kung-I
authors.initials: KI
authors.lastname: Feng
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Boyce
authors.forename: Robert G
authors.initials: RG
authors.lastname: Aslanian
authors.forename: Jai
authors.initials: J
authors.lastname: Palamanda
authors.forename: Amin A
authors.initials: AA
authors.lastname: Nomeir
authors.forename: Walter
authors.initials: W
authors.lastname: Korfmacher
authors.forename: John C
authors.initials: JC
authors.lastname: Hunter
authors.forename: John C
authors.initials: JC
authors.lastname: Anthes
authors.forename: John A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D000322:Adrenergic Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008297:Male; D008782:Methylurea Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009297:Nasal Mucosa / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000819:agonists / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects* / Q000378:metabolism; D013552:Swine
chemical_list: D000322:Adrenergic Agonists; D008782:Methylurea Compounds; D009025:Morpholines; C558244:N-(3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1,4-benzoxazin-6-yl)-N-ethyl-N'-methylurea; D018341:Receptors, Adrenergic, alpha-2; D011994:Recombinant Proteins