172899-78-4Relevant articles and documents
Design, parallel synthesis, and crystal structures of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
Parlow, John J.,Case, Brenda L.,Dice, Thomas A.,Fenton, Ricky L.,Hayes, Michael J.,Jones, Darin E.,Neumann, William L.,Wood, Rhonda S.,Lachance, Rhonda M.,Girard, Thomas J.,Nicholson, Nancy S.,Clare, Michael,Stegeman, Roderick A.,Stevens, Anna M.,Stallings, William C.,Kurumbail, Ravi G.,South, Michael S.
, p. 4050 - 4062 (2007/10/03)
Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor VIIa (TF/VIIa) complex. The crystal structure of a tripeptide-α-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S1, S2, and S3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P1, P2, and P3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/VIIa with excellent selectivity over thrombin (IIa) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.
Design and synthesis of benzoic acid derivatives as influenza neuraminidase inhibitors using structure-based drug design
Chand, Pooran,Babu, Yarlagadda S.,Bantia, Shanta,Chu, Naiming,Cole, L. Brent,Kotian, Pravin L.,Laver, W. Graeme,Montgomery, John A.,Pathak, Ved P.,Petty, Sandra L.,Shrout, David P.,Walsh, David A.,Walsh, Gerald M.
, p. 4030 - 4052 (2007/10/03)
A series of 94 benzoic acid derivatives was synthesized and tested for its ability to inhibit influenza neuraminidase. The enzyme-inhibitor complex structure was determined by X-ray crystallographic analysis for compounds which inhibited the enzyme. The most potent compound tested in vitro, 5 (4- (acetylamino)-3-guanidinobenzoic acid), had an IC50 = 2.5 x 10-6 M against N9 neuraminidase. Compound 5 was oriented in the active site of the neuraminidase in a manner that was not predicted from the reported active site binding of GANA (4) with neuraminidase. In a mouse model of influenza, 5 did not protect the mice from weight loss due to the influenza virus when dosed intranasally.
