title: Synthesis and pharmacological investigation of azaphthalazinone human histamine H(1) receptor antagonists.
abstract: 5-Aza, 6-aza, 7-aza and 8-aza-phthalazinone, and 5,8-diazaphthalazinone templates were synthesised by stereoselective routes starting from the appropriate pyridine/pyrazine dicarboxylic acids by activation with CDI, reaction with 4-chlorophenyl acetate ester enolate to give a β-ketoester, which was hydrolysed, and decarboxylated. The resulting ketone was condensed with hydrazine to form the azaphthalazinone core. The azaphthalazinone cores were alkylated with N-Boc-D-prolinol at N-2 by Mitsunobu reaction, de-protected, and then alkylated at the pyrrolidine nitrogen to provide the target H(1) receptor antagonists. All four mono-azaphthalazinone series had higher affinity (pK(i)) for the human H(1) receptor than azelastine, but were not as potent as the parent non-aza phthalazinone. The 5,8-diazaphthalazinone was equipotent with azelastine. The least potent series were the 7-azaphthalazinones, whereas the 5-azaphthalazinones were the most lipophilic. The more hydrophilic series were the 8-aza series. Replacement of the N-methyl substituent on the pyrrolidine with the n-butyl group caused an increase in potency (pA(2)) and a corresponding increase in lipophilicity. Introduction of a β-ether oxygen in the n-butyl analogues (2-methoxyethyl group) decreased the H(1) pA(2) slightly, and increased the selectivity against hERG. The duration of action in vitro was longer in the 6-azaphthalazinone series. The more potent and selective 6-azaphthalazinone core was used to append an H(3) receptor antagonist fragment, and to convert the series into the long acting single-ligand, dual H(1) H(3) receptor antagonist 44. The pharmacological profile of 44 was very similar to our intranasal clinical candidate 1.
authors.affiliation: Medicinal Chemistry, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. pan.a.procopiou@gsk.com
authors.forename: Panayiotis A
authors.initials: PA
authors.lastname: Procopiou
authors.forename: Christopher
authors.initials: C
authors.lastname: Browning
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gore
authors.forename: Sean M
authors.initials: SM
authors.lastname: Lynn
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Richards
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Slack
authors.forename: Steven L
authors.initials: SL
authors.lastname: Sollis
mesh_terms: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000737:chemistry* / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C578262:4-((4-chlorophenyl)methyl)-2-((1-(4-(4-((3-(hexahydro-1H-azepin-1-yl)propyl)oxy)phenyl)butyl)-2-pyrrolidinyl)methyl)pyrido(3,4-d)pyridazin-1(2H)-one; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D006634:Histamine H1 Antagonists; C000606913:KCNH2 protein, human; D010793:Phthalazines; D011719:Pyrazines; D011724:Pyridazines; D011725:Pyridines; D011969:Receptors, Histamine H1; C023666:pyridine; C020976:azelastine