Synthesis and structure-activity relationships of novel histamine H1 antagonists: indolylpiperidinyl benzoic acid derivatives.
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.
Fonquerna
Silvia
S
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024-Barcelona, Spain. sfonquerna@almirall.es
Miralpeix
Montse
M
Pagès
Lluís
L
Puig
Carles
C
Cardús
Arantxa
A
Antón
Francisca
F
Cárdenas
Alvaro
A
Vilella
Dolors
D
Aparici
Mónica
M
Calaf
Elena
E
Prieto
José
J
Gras
Jordi
J
Huerta
Josep M
JM
Warrellow
Graham
G
Beleta
Jorge
J
Ryder
Hamish
H
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
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