Synthesis and evaluation of N-acylsulfonamide and N-acylsulfonylurea prodrugs of a prostacyclin receptor agonist.
N-Acylsulfonamide and N-acylsulfonylurea derivatives of the carboxylic acid prostacyclin receptor agonist 1 were synthesized and their potential as prodrug forms of the carboxylic acid was evaluated in vitro and in vivo. These compounds were converted to the active compound 1 by hepatic microsomes from rats, dogs, monkeys, and humans, and some of the compounds were shown to yield sustained plasma concentrations of 1 when they were orally administered to monkeys. These types of analogues, including NS-304 (2a), are potentially useful prodrugs of 1.
Nakamura
Akio
A
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd, 14 Nishinosho-Monguchi-Cho, Kisshoin, Minami-Ku, Kyoto 601 8550, Japan.
Yamada
Tetsuhiro
T
Asaki
Tetsuo
T
D000081:Acetamides / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D011464:Epoprostenol / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D000882:Haplorhini; D006801:Humans; D008297:Male; D008861:Microsomes / Q000378:metabolism; D015394:Molecular Structure; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011719:Pyrazines / Q000097:blood / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044006:Receptors, Epoprostenol / Q000819:agonists*; D013453:Sulfonylurea Compounds / Q000737:chemistry*
D000081:Acetamides; D010975:Platelet Aggregation Inhibitors; D011355:Prodrugs; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D013453:Sulfonylurea Compounds; C523468:selexipag; D011464:Epoprostenol