131724-45-3Relevant articles and documents
Peripheral Selective Oxadiazolylphenyl Alanine Derivatives as Tryptophan Hydroxylase 1 Inhibitors for Obesity and Fatty Liver Disease
Bae, Eun Jung,Choi, Won Gun,Pagire, Haushabhau S.,Pagire, Suvarna H.,Parameswaran, Saravanan,Choi, Jun-Ho,Yoon, Jihyeon,Choi, Won-Il,Lee, Ji Hun,Song, Jin Sook,Bae, Myung Ae,Kim, Mijin,Jeon, Jae-Han,Lee, In-Kyu,Kim, Hail,Ahn, Jin Hee
, p. 1037 - 1053 (2021/02/05)
Tryptophan hydroxylase 1 (TPH1) has been recently suggested as a promising therapeutic target for treating obesity and fatty liver disease. A new series of 1,2,4-oxadiazolylphenyl alanine derivatives were identified as TPH1 inhibitors. Among them, compound 23a was the most active in vitro, with an IC50 (half-maximal inhibitory concentration) value of 42 nM, showed good liver microsomal stability, and showed no significant inhibition of CYP and hERG. Compound 23a inhibited TPH1 in the peripheral tissue with limited BBB penetration. In high-fat diet-fed mice, 23a reduced body weight gain, body fat, and hepatic lipid accumulation. Also, 23a improved glucose intolerance and energy expenditure. Taken together, compound 23a shows promise as a therapeutic agent for the treatment of obesity and fatty liver diseases.
A new strategy for the development of highly potent and selective plasmin inhibitors
Saupe, Sebastian M.,Steinmetzer, Torsten
supporting information; experimental part, p. 1171 - 1180 (2012/04/17)
A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with Ki of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.
Fluorobenzamidrazone thrombin inhibitors: Influence of fluorine on enhancing oral absorption
Lee, Koo,Jung, Won-Hyuk,Sang, Yeul Hwang,Lee, Sung-Hack
, p. 2483 - 2486 (2007/10/03)
LB30057 (1) is a selective and efficacious oral thrombin inhibitor. Fluorine-substitution on the phenylene ring of the benzamidrazone portion in both compound 1 and its derivatives gave, in many cases, enhanced oral absorption in rats while maintaining the intrinsic potency and selectivity. Compound 2 demonstrated a 3-fold increase in absorption.
