Jefferson R. McCowan

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.

Fused bicyclic Gly-Asp β-turn mimics with potent affinity for GPIIb-IIIa. Exploration of the arginine isostere

6-[4-Amidinobenzoyl]amino]-tetralone-2-acetic acid is a potent antagonist of GPIIb-IIIa. Substitution in the meta position of the benzamidine, or replacement with a heteroaryl amidine was tolerated in this series. Use of an acyl-linked 4-alkyl piperidine as an arginine isostere also provided active compounds. Compounds from this series provided substantial systemic exposure in the rat following oral administration.

SOLID PHASE CHEMISTRY APPROACH TO THE SAR DEVELOPMENT OF A NOVEL CLASS OF ACTIVE SITE-DIRECTED THROMBIN INHIBITORS

Abstract A solid phase chemistry approach utilizing Mitsunobu chemistry, amine functionalization, and parallel purification was used to produce a diverse library of benzothiophene analogs. These analogs were used to advance the SAR of this class of molecules and give new directions for future studies.

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.

Enzymic and nonenzymic lipid peroxidation: inhibition by substituted phenoxazines

Abstract A series of phenoxazines was evaluated as in vitro inhibitors of 5-lipoxygenase (5-LO) and iron-dependent lipid peroxidation. A linear relationship (r2 = 0.91, n = 10) was found for the ester, hydroxamic acid and C-1 carboxylic acid representatives suggesting that hydroxamic acid mediated iron chelation may not contribute significantly to 5-LO inhibition by these compounds.

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.

Structurally novel antiarrhythmic / antioxidant quinazolines

Abstract We report a structurally novel series of quinazolines with in vivo antiarrhythmic and/or in vitro iron-dependent lipid peroxidation inhibitory activity. Two analogues, 7 and 12, were evaluated in a canine model of regional myocardial ischemia and reperfusion.

Phenothiazine and phenoxazine derivatives of nafazatrom. In vitro evaluation as 5-lipoxygenase and iron-dependent lipid peroxidation inhibitors.

Abstract A series of phenothiazine and phenoxazine analogs of nafazatrom were prepared and evaluated as 5-lipoxygenase and iron-dependent lipid peroxidation inhibitors (rabbit brain homogenate) in vitro. Nafazatrom and two representatives from the described series were also evaluated as peroxyl radical and superoxide anion scavengers.