Investigation of binding proteins for anti-platelet agent K-134 by Drug-Western method.

K-134 ((-)-6-[3-[3-cyclopropyl-3-[(1R, 2R)-2-hydroxycyclohexyl]ureido]-propoxy]-2(1H)-quinolinone) is a novel anti-platelet agent with anti-hyperplastic activities. We found previously that K-134 is a potent phosphodiesterase-3 (PDE3) inhibitor. In the present study, we found other K-134-binding proteins by Drug-Western method.

A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels.

Background: Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1), a major ACAT isozyme in macrophages, plays an essential role in foam cell formation in atherosclerotic lesions. However, whether pharmacological inhibition of macrophage ACAT-1 causes exacerbation or suppression of atherosclerosis is controversial.

Methods And Results: We developed and characterized a novel ACAT inhibitor, K-604.

HMN-176, an active metabolite of the synthetic antitumor agent HMN-214, restores chemosensitivity to multidrug-resistant cells by targeting the transcription factor NF-Y.

HMN-176 ((E)-4-[[2-N-[4-methoxybenzenesulfonyl]amino]stilbazole]1-oxide) is an active metabolite of HMN-214 ((E)-4-[2-[2-(N-acetyl-N-[4-methoxybenzenesulfonyl]amino)stilbazole]]1-oxide), which has a potent antitumor activity in mouse xenograft models. In this study, we show that HMN-176 circumvents multidrug resistance in a K2 human ovarian cancer subline selected for Adriamycin resistance (K2/ARS). Upon treatment of K2/ARS cells with 3 microM HMN-176, the GI(50) of Adriamycin for the cells decreased by approximately 50%.

Inhibition of rho-kinase-induced myristoylated alanine-rich C kinase substrate (MARCKS) phosphorylation in human neuronal cells by H-1152, a novel and specific Rho-kinase inhibitor.

The functions of small G protein Rho-associated kinase (Rho-kinase) have been determined in muscle and non-muscle cells, but, particularly in neuronal cells, its effector(s) has not been well known. Recently, we preliminarily reported that Rho-kinase phosphorylates the Ser159 residue in myristoylated alanine-rich C kinase substrate (MARCKS) in vitro, but it remains obscure in vivo. To further clarify this point, we developed an isoquinolinesulfonamide derivative, H-1152, that is a more specific, stronger and membrane-permeable inhibitor of Rho-kinase with a Ki value of 1.