title: H3-receptor antagonists: synthesis and structure-activity relationships of para- and meta-substituted 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazoles.
abstract: We report the synthesis, octanol/water partition coefficient (log P), dissociation constants (pKa), H3-receptor affinity (pKi in rat brain membranes, [3H]-N alpha-methylhistamine), and H3-antagonist potency (pA2 in guinea ileum, (R)-alpha-methylhistamine) of novel H3-receptor antagonists obtained by introducing a para or meta substituent on the phenyl ring of the lead compound 4(5)-phenyl-2-[[2-[4(5)-imidazolyl]ethyl]thio]imidazole (3a). The substituents were chosen to obtain broad and uncorrelated variation in their lipophilic, electronic, and steric properties. The log P values of the neutral species cover almost 3 orders of magnitude (from 1.40 to 4.11). The pKa,2 values (protonation of the 2-thioimidazole fragment) vary from 3.13 to 4.34, indicating that this fragment, which incorporates the so-called polar group common to many H3-receptor antagonists, is neutral at physiological pH. The compounds had pKi values in a range too narrow (from 7.28 to 8.03) to derive QSAR equations. In one case (3g), a biphasic displacement curve was observed (pKi,1 = 8.53; pKi,2 = 6.90). The pA2 values ranged 2 orders of magnitude (from 6.83 to 8.87) and yielded a QSAR model (PLS) indicating that antagonist potency depends parabolically on lipophilicity and is decreased by bulky para substituents. The compounds of this series, therefore, maintain a fair-to-good affinity for rat brain H3-receptor and a fair-to-good H3-antagonist potency on guinea pig ileum, although varying markedly in their lipophilicity. The series thus appears as a good candidate for pharmacokinetic optimization leading to brain-penetrating H3-receptor antagonists.
authors.affiliation: Dipartimento Farmaceutico, Università degli Studi di Parma, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Mor
authors.forename: F
authors.initials: F
authors.lastname: Bordi
authors.forename: C
authors.initials: C
authors.lastname: Silva
authors.forename: S
authors.initials: S
authors.lastname: Rivara
authors.forename: P
authors.initials: P
authors.lastname: Crivori
authors.forename: P V
authors.initials: PV
authors.lastname: Plazzi
authors.forename: V
authors.initials: V
authors.lastname: Ballabeni
authors.forename: A
authors.initials: A
authors.lastname: Caretta
authors.forename: E
authors.initials: E
authors.lastname: Barocelli
authors.forename: M
authors.initials: M
authors.lastname: Impicciatore
authors.forename: P A
authors.initials: PA
authors.lastname: Carrupt
authors.forename: B
authors.initials: B
authors.lastname: Testa
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D017259:Dimaprit / Q000494:pharmacology; D004558:Electric Stimulation; D005071:Evoked Potentials; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D007082:Ileum / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D008761:Methylhistamines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C069357:alpha-methylhistamine; D017259:Dimaprit