First steps in the direction of synthetic, allosteric, direct inhibitors of thrombin and factor Xa

Abstract

Designing non-saccharide functional mimics of heparin is a major challenge. In this work, a library of small, aromatic molecules based on the sulfated DHP scaffold was synthesized and screened against thrombin and factor Xa. The results reveal that i) selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly; ii) the two enzymes recognize different structural features in the benzofurans studied suggesting significant selectivity of recognition; and iii) the mechanism of inhibition is allosteric. The molecules represent the first allosteric small molecule inhibitors of the two enzymes.

Rational Design of Potent, Small, Synthetic Allosteric Inhibitors of Thrombin

“…Of the 15 sulfated monomers studied in this work and 17 sulfated and unsulfated monomers studied earlier, 23 only 5i inhibited thrombin with measurable potency (~500 μM, Table 1). By contrast, most sulfated dimers displayed thrombin inhibition (Table 2).…”

Chemical sulfation of small molecules—advances and challenges

“…For example, several large and small aromatic H/HS mimetics including sulfated flavonoids27,28, benzofurans29, isoquinolines30 and sulfated dehydropolymers of the lignin-type31,32 have been designed to modulate the function of coagulation proteins such as antithrombin, thrombin and factor Xa. The design of such highly sulfated, non-natural molecules suggests a strong possibility of discovering novel sulfated non-carbohydrate pharmaceutical agents.…”

Combinatorial Chemistry Online

“…The results reveal that selected monomeric benzofuran derivatives inhibit the two enzymes, albeit weakly, and that the mechanism of inhibition is allosteric. 16 The discovery and parallel synthesis of potent, small molecule antagonists of the Neuromedin B receptor based on the aryl-hexahydro-dibenzodiazepin-1-one core has been described. 17 A series of libraries were designed using the 1-(cyclopropylmethyl) -2-alkyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-5-ium template, and a number of sulphonamide derivatives proved to be potent agonists of the CB 2 receptor.…”