title: A novel series of histamine H4 receptor antagonists based on the pyrido[3,2-d]pyrimidine scaffold: comparison of hERG binding and target residence time with PF-3893787.
abstract: In this work we describe the optimization of a lead compound based on the quinazoline template to give a new series of potent pyrido[3,2-d]pyrimidines as histamine H4 receptor antagonists. The pyrido[3,2-d]pyrimidine ligands have significantly reduced hERG binding compared to clinical stage compound PF-3893787 while showing good affinities at the human and rodent histamine receptors. The receptor residence time of several of these new compounds was determined for the human H4R and compared with JNJ7777120 and PF-3893787. The pyrido[3,2-d]pyrimidines showed residence times lower than JNJ7777120 but comparable to the residence time of PF-3893787. Overall, the pyrido[3,2-d]pyrimidines show an excellent in vitro profile that warrants their further investigation in relevant models of human disease.
authors.affiliation: Griffin Discoveries BV, Department of Medicinal Chemistry, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
authors.forename: Mounir
authors.initials: M
authors.lastname: Andaloussi
authors.forename: Herman D
authors.initials: HD
authors.lastname: Lim
authors.forename: Tiffany
authors.initials: T
authors.lastname: van der Meer
authors.forename: Maarten
authors.initials: M
authors.lastname: Sijm
authors.forename: Chris B M
authors.initials: CB
authors.lastname: Poulie
authors.forename: Iwan J P
authors.initials: IJ
authors.lastname: de Esch
authors.forename: Rob
authors.initials: R
authors.lastname: Leurs
authors.forename: Rogier A
authors.initials: RA
authors.lastname: Smits
mesh_terms: D000818:Animals; D002460:Cell Line; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000737:chemistry / Q000378:metabolism*; D006207:Half-Life; D006633:Histamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000493:pharmacokinetics; D007700:Kinetics; D051379:Mice; D010879:Piperazines / Q000737:chemistry / Q000493:pharmacokinetics; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011968:Receptors, Histamine / Q000378:metabolism; D000074040:Receptors, Histamine H4; D013329:Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C418607:HRH4 protein, human; D006633:Histamine Antagonists; D007211:Indoles; C000606913:KCNH2 protein, human; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D011759:Pyrrolidines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C574730:pyrido(3,2-d)pyrimidine; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; C569544:PF-3893787