title: Synthesis and structure-activity relationships of novel histamine H1 antagonists: indolylpiperidinyl benzoic acid derivatives.
abstract: A series of indolylpiperidinyl derivatives were prepared and evaluated for their activity as histamine H(1) antagonists. Structure-activity relationship studies were directed toward improving in vivo activity and pharmacokinetic profile of our first lead (1). Substitution of fluorine in position 6 on the indolyl ring led to higher in vivo activity in the inhibition of histamine-induced cutaneous vascular permeability assay but lower selectivity toward 5HT(2) receptor. Extensive optimization was carried out within this series and a number of histamine H(1) antagonists showing potency and long duration of action in vivo and low brain penetration or cardiotoxic potential were identified. Within this novel series, indolylpiperidines 15, 20, 48,51 and 52 exhibited a long half-life in rat and have been selected for further preclinical evaluation.
authors.affiliation: Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024-Barcelona, Spain. sfonquerna@almirall.es
authors.forename: Silvia
authors.initials: S
authors.lastname: Fonquerna
authors.forename: Montse
authors.initials: M
authors.lastname: Miralpeix
authors.forename: Lluís
authors.initials: L
authors.lastname: Pagès
authors.forename: Carles
authors.initials: C
authors.lastname: Puig
authors.forename: Arantxa
authors.initials: A
authors.lastname: Cardús
authors.forename: Francisca
authors.initials: F
authors.lastname: Antón
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cárdenas
authors.forename: Dolors
authors.initials: D
authors.lastname: Vilella
authors.forename: Mónica
authors.initials: M
authors.lastname: Aparici
authors.forename: Elena
authors.initials: E
authors.lastname: Calaf
authors.forename: José
authors.initials: J
authors.lastname: Prieto
authors.forename: Jordi
authors.initials: J
authors.lastname: Gras
authors.forename: Josep M
authors.initials: JM
authors.lastname: Huerta
authors.forename: Graham
authors.initials: G
authors.lastname: Warrellow
authors.forename: Jorge
authors.initials: J
authors.lastname: Beleta
authors.forename: Hamish
authors.initials: H
authors.lastname: Ryder
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006207:Half-Life; D006634:Histamine H1 Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051379:Mice; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012867:Skin / Q000098:blood supply; D013329:Structure-Activity Relationship
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D007211:Indoles; D010880:Piperidines; D018340:Receptors, Adrenergic, alpha-1; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A