Tiplaxtinin, a Novel, Orally Efficacious Inhibitor of Plasminogen Activator Inhibitor‐1: Design, Synthesis, and Preclinical Characterization.

Abstract

a mixture of 4 (5.8 g, 20.3 mmol), 4-trifluoromethoxyphenylboronic acid (6.38 g, 30.4 mmol), potassium carbonate (7.05 g, 50.75 mmol), palladium(II) acetate (0.029 g) and tetrabutylammonium bromide (Aldrich, 6.5 g, 20.3 mmol) in 15 % dioxane in water (degassed, 200 mL) was stirred at 75 °C for about 36 hours. The reaction was monitored by TLC. After all 1-benzyl-5-bromo-1H-indole was consumed, the reaction was cooled and the solvent was decanted. The residual gum was extracted with hexane (2 X ~ 400 mL; following stirring for few hours). The combined hexane extracts were washed with water and filtered. This filtrate was evaporated to afford a solid. The solid was crystallized from petroleum ether to give compound 5 as a white solid (6.0 g, 80%), mp: 62-63 o C. Mass spectrum (+ESI, [M+H] + ) m/z 368; 1

On the role of plasminogen activator inhibitor‐1 in adipose tissue development and insulin resistance in mice

“…It cannot be excluded that the effect of PAI-1 is dose-dependent such as was observed previously in mouse models, where PAI-1 at physiological concentration promoted tumor development, whereas invasion and vascularization were inhibited at pharmacological concentrations [23]. The interaction of PAI-039 with PAI-1 has previously been studied in detail [15,16], and it was shown to have a good oral bioavailability in mice and to be effective in protecting apolipoprotein E deficient mice against atherosclerosis [24,25]. In this study, a dose of 1 mg g )1 food was well tolerated, without apparent side effects.…”

“…Age-matched (45-55 weeks) male WT mice or transgenic mice overexpressing murine PAI-1 (PAI-1 Tg) under control of the adipocyte aP2 promotor [11] (genetic background 50% C57Bl/6: 50% FVB), were kept in microisolation cages on a 12 h day-night cycle and fed water and a standard fat diet (KM-04-k12, Muracon, Carfil; containing 13% kcal as fat, with a caloric value of 10.9 kJ g )1 ). The low M r PAI-1 inhibitor tiplaxtinin (PAI-039) (C 24 H 16 F 3 NO 4 ) was obtained from Wyeth Research (Collegeville, PA, USA) [15,16]. One group of animals (n ¼ 12) was given the inhibitor (1 mg g )1 food) for 4 weeks, while a second group (n ¼ 12) was continued on normal food.…”

Plasminogen activator inhibitor‐1 as regulator of tumor‐initiating cell properties in head and neck cancers

“…Tiplaxtinin (also named as PAI-039) is an indole oxoacetic acid derivative and exhibited oral efficacy in the animal models of acute arterial thrombosis in vivo. 23 Recently, PAI-039 also displayed anti-angiogenesis and antitumor growth activities in the human bladder cancer xenograft model in vivo. 24 For the present study, we investigated the effect of PAI-039 on head and neck cancer-TICs derived from PAI-1 expressing human HNSCC cell lines.…”

Effect of pharmacologic plasminogen activator inhibitor‐1 inhibition on cell motility and tumor angiogenesis

“…Furthermore, the absence of host PAI-1 has been demonstrated to prevent cancer invasion and vascularization [10]. Our recent discovery of a small molecule PAI-1 inhibitor, PAI-039 [11], has provided a pharmacologic tool to further investigate the role of PAI-1 inhibition in tissue remodeling and confirm the involvement of PAI-1 in cell adhesion, migration and angiogenesis. site-directed mutagenesis.…”

“…PAI-1 concentrations were determined from previously performed dose responses (data not shown). PAI-039 is a novel, orally active PAI-1 inhibitor previously shown to have both in vitro and in vivo efficacy [11]. This compound was synthesized at Wyeth Research.…”