Diamino Benzo[b]thiophene Derivatives as a Novel Class of Active Site Directed Thrombin Inhibitors. 5. Potency, Efficacy, and Pharmacokinetic Properties of Modified C-3 Side Chain Derivatives

Abstract

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.

Direct thrombin inhibitors – a survey of recent developments

“…Indeed, several potent inhibitors have been identified that include P1 groups such as aminoalkyl, aminocyclohexyl [137,187,188], aminopyridine [32,138,153,185,189], aminopyridazine [185], aminopyrimidine [185], aminopyrazine [185], benzamidrazone [190,191], thienylamidine [133], azaphenylalanine [192], 4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine, 4,5,6,7-tetrahydro-2H-indazole and 2-imino-4,5,6,7-tetrahydro-1,3-benzothiazol-3(2H)-yl-amine [193]. Furthermore, there are also a few examples of neutral P1 moieties such as benzothiophene and hydroxybenzothiophene [194][195][196], cyclohexylmethyl, benzyl and dichlorobenzyl [197], 3-chlorobenzyl and 2-oxyacetamide-5-chlorobenzyl [38,198], phenol [33], tryptophan [199] and 6-fluorotryptamine [200]. As one of the most recent examples, screening of a fragment-based compound library also resulted in the discovery of thrombin-binding fragments with a nonbasic P1 motif [201].…”

“…However, only some chlorobenzyl-based inhibitors and a few hydroxybenzothiophene derivatives such as inhibitor 42 (K i = 0.3 nM; Fig. 13) [194][195][196] exhibited low-nanomolar inhibition constants. Recently, a new series of thrombin inhibitors containing D-tyrosine at the P1 position, was identified by a novel computer-assisted multiparameter optimization approach [37] based on a new type of algorithm developed by M. Thürk (Matrix Advanced Solutions Germany GmbH).…”

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

“…Optimization resulted in compounds, such as 115 (K i =0.3 nM) and 116 (K i = 0.5 nM), which were highly potent in clotting assays in vitro. In contrast, these inhibitors suffered from relatively poor in vivo efficacy due to rapid and extensive distribution in various tissues making them less available to inhibit thrombin in plasma [156,157].…”

A novel base-promoted cyclization: synthesis of substituted benzo[b]furans

“…1-4 For example, the benzofuran moiety is found in antidepressant (-)-BPAP, 5 angiotensin II inhibitors, 6 5-lipoxygenase inhibitors, 6 nerokinin-2 receptor antagonist, 7 cathepsin K inhibitors, 3 and calcium entry blockers. In addition, there are also many benzofuran-containing natural products including (−)-concentricolide, 8 (+)-frondosin B 9 and the eupomatenoid family.…”