Michael L. Denney

Dibasic benzo[b]thiophene derivatives as A novel class of active site directed thrombin inhibitors : 4. SAR studies on the conformationally restricted C3-side chain of hydroxybenzo[b]thiophenes

A novel series of benzo[b]thiophene diamine thrombin inhibitors with a conformationally restricted C3-side chain 3 was investigated. The constrained C3-side chain by a cyclohexyl ring contributed to not only an additive but also a synergistic effect on the thrombin inhibitory activity. The SAR studies resulted in the discovery of a potent thrombin inhibitor 27 that was over 750-fold more potent than the initial lead compound 1.

Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors: 2. Sidechain optimization and demonstration of in vivo efficacy.

Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis.

Platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa) antagonists derived from amidinoindoles

Abstract A series of substituted amidinoindoles have been prepared as mimics of the RGD sequence and were studied as antagonists of the platelet glycoprotein IIb–IIIa receptor (GPIIb–IIIa). The agents were potent and selective antagonists of GPIIb–IIIa. Compared to their acyclic counterparts, the amidinoindole series bound with 10- to 20-fold greater affinity, indicating the advantages of added conformational restriction and/or hydrophobicity in the basic region of RGD mimics.

Characterization of LY806303 as a potent and selective inhibitor of thrombin

Abstract Methyl 3-(2-methyl-1-oxopropoxy)[1]benzothieno[3,2-b]furan-2-carboxylate (LY806303; 1) has been characterized as a novel, potent and selective inhibitor thrombin.