title: Synthesis and evaluation of a new series of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives as high affinity and selective histamine-3 receptor (H3R) antagonists.
abstract: A novel class of 1'-cyclobutyl-6-(4-piperidyloxy)spiro[benzopyran-2,4'-piperidine] derivatives with low nanomolar affinity for the human and rat histamine-3 receptors (H(3)Rs) are described. The spirobenzopyran piperidine ether analogs demonstrated excellent H(3)R affinity and selectivity against histamine receptor subtypes (H(1)R, H(2)R, and H(4)R), were stable in liver microsomes, and had selectivity against CYP P450 enzymes. Compounds 10, 13, 15, and 16 demonstrated high H(3)R affinity, in vitro liver microsomal stability, selectivity against CYP isoforms, moreover, these ether analogs exhibited acceptable iv pharmacokinetic (PK) properties but had poor oral exposure in rat.
authors.affiliation: Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rdandu1321@gmail.com
authors.forename: Reddeppa Reddy
authors.initials: RR
authors.lastname: Dandu
authors.forename: Jacquelyn A
authors.initials: JA
authors.lastname: Lyons
authors.forename: Rita
authors.initials: R
authors.lastname: Raddatz
authors.forename: Zeqi
authors.initials: Z
authors.lastname: Huang
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Aimone
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hudkins
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001578:Benzopyrans; D006633:Histamine Antagonists; D010880:Piperidines; D018100:Receptors, Histamine H3; D013141:Spiro Compounds; D003577:Cytochrome P-450 Enzyme System