308846-62-0Relevant articles and documents
Optimization of Substrate-Analogue Furin Inhibitors
Ivanova, Teodora,Hardes, Kornelia,Kallis, Stephanie,Dahms, Sven O.,Than, Manuel E.,Künzel, Sebastian,B?ttcher-Friebertsh?user, Eva,Lindberg, Iris,Jiao, Guan-Sheng,Bartenschlager, Ralf,Steinmetzer, Torsten
, p. 1953 - 1968 (2017)
The proprotein convertase furin is a potential target for drug design, especially for the inhibition of furin-dependent virus replication. All effective synthetic furin inhibitors identified thus far are multibasic compounds; the highest potency was found for our previously developed inhibitor 4-(guanidinomethyl)phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148). An initial study in mice revealed a narrow therapeutic range for this tetrabasic compound, while significantly reduced toxicity was observed for some tribasic analogues. This suggests that the toxicity depends at least to some extent on the overall multibasic character of this inhibitor. Therefore, in a first approach, the C-terminal benzamidine of MI-1148 was replaced by less basic P1 residues. Despite decreased potency, a few compounds still inhibit furin in the low nanomolar range, but display negligible efficacy in cells. In a second approach, the P2 arginine was replaced by lysine; compared to MI-1148, this furin inhibitor has slightly decreased potency, but exhibits similar antiviral activity against West Nile and Dengue virus in cell culture and decreased toxicity in mice. These results provide a promising starting point for the development of efficacious and well-tolerated furin inhibitors.
Design, synthesis, and biological evaluation of pyrazinones containing novel P1 needles as inhibitors of TF/VIIa
Trujillo, John I.,Huang, Horng-Chih,Neumann, William L.,Mahoney, Matthew W.,Long, Scott,Huang, Wei,Garland, Danny J.,Kusturin, Carrie,Abbas, Zaheer,South, Michael S.,Reitz, David B.
, p. 4568 - 4574 (2008/02/11)
Herein is described the design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors were designed to explore replacement and variation of the P1 amidine described previously [J. Med. Chem. 2003, 46, 4050]. The P1 needle replacements were selected based upon their reduced basicity compared to the parent phenyl amidine (pKa ～ 12). A contributing factor towards the oral bioavailability of a compound is the ionization state of the compound in the intestinal tract. The desired outcome of the study was to identify an orally bioavailable TF-VIIa inhibitor.
Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: Discovery of N-carboxymethyl-D-diphenylalanyl-L-prolyl[(5-amidino-2- thienyl)methyllamide
Lee, Koo,Park, Cheol Won,Jung, Won-Hyuk,Park, Hee Dong,Lee, Sun Hwa,Chung, Kyung Ha,Park, Su Kyung,Kwon, O. Hwan,Kang, Myunggyun,Park, Doo-Hee,Lee, Sang Koo,Kim, Eunice E.,Yoon, Suk Kyoon,Kim, Aeri
, p. 3612 - 3622 (2007/10/03)
Thrombin, a crucial enzyme in the blood coagulation, has been a target for antithrombotic therapy. Orally active thrombin inhibitors would provide effective and safe prophylaxis for venous and arterial thrombosis. We conducted optimization of a highly efficacious benzamidine-based thrombin inhibitor LB30812 (3, Ki = 3 pM) to improve oral bioavailability. Of a variety of arylamidines investigated at the P1 position, 2,5-thienylamidine effectively replaced the benzamidine without compromising the thrombin inhibitory potency and oral absorption. The sulfamide and sulfonamide derivatization at the N-terminal position in general afforded highly potent thrombin inhibitors but with moderate oral absorption, while the well-absorbable N-carbamate derivatives exhibited limited metabolic stability in S9 fractions. The present work culminated in the discovery of the N-carboxymethyl- and 2,5-thienylamidine-containing compound 22 that exhibits the most favorable profiles of anticoagulant and antithrombotic activities as well as oral bioavilability (Ki = 15 pM; F = 43%, 42%, and 15% in rats, dogs, and monkeys, respectively). This compound on a gravimetric basis was shown to be more effective than a low molecular weight heparin, enoxaparin, in the venous thrombosis models of rat and rabbit. Compound 22 (LB30870) was therefore selected for further preclinical and clinical development.
