title: Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 3. Synthesis and biological activities of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives and related compounds.
abstract: A novel series of oxazolecarboxamide-substituted omega-phenyl-omega-(3-pyridyl)alkenoic acid derivatives was discovered as potent dual-acting agents to block the TXA2 receptor and to inhibit the thromboxane synthase (TRA/TSI). Synthesis, structure-activity relationship (SAR), and in vitro and in vivo pharmacology of this series of compounds are described. Modification of the series revolved around the oxazole moiety to increase the hydrophilicity of the compounds and to correlate the biological activity with lipophilicity of the compounds. The most potent in the series was (E)-7-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl] phenyl]-7 -(3-pyridyl)hept-6-enoic acid (14) with Kd = 9.9 +/- 0.4 nM for the thromboxane receptor antagonism and IC50 = 55.0 +/- 17.9 nM for thromboxane synthase inhibition. The compound 14 was a selective TRA/TSI which exhibited desirable characteristics for oral activity, "shunt" effect to elevate PGI2 level, and absence of agonist activity.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
authors.forename: K
authors.initials: K
authors.lastname: Takeuchi
authors.forename: T J
authors.initials: TJ
authors.lastname: Kohn
authors.forename: T A
authors.initials: TA
authors.lastname: True
authors.forename: D E
authors.initials: DE
authors.lastname: Mais
authors.forename: J H
authors.initials: JH
authors.lastname: Wikel
authors.forename: B G
authors.initials: BG
authors.lastname: Utterback
authors.forename: V L
authors.initials: VL
authors.lastname: Wyss
authors.forename: J A
authors.initials: JA
authors.lastname: Jakubowski
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D006538:Heptanoic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010080:Oxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
chemical_list: C116712:7-(4-(4-(((4-cyclohexylbutyl)amino)carbonyl)-2-oxazolyl)phenyl)-7-(3-pyridyl)hept-6-enoic acid; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D010080:Oxazoles; D017482:Receptors, Thromboxane; D013929:Thromboxane B2; D011464:Epoprostenol; D013930:Thromboxane-A Synthase