Hans Lucas

Syntheses of heparin-like pentamers containing opened uronic acid moieties

Abstract The syntheses of four analogues of pentasaccharide Ia , which corresponds to the minimal AT III binding region of heparin, are presented and the biological activities of these analogues will be discussed. Three of these analogues (i.e. compounds II , III and IV ) contain an R -glyceric acid oxymethylene residue ( i.e. B in fig.3 ) instead of α-L-iduronic acid and in the other analogue ( i.e. compound V ) the β-D-glucuronic acid unit has been replaced by an s -glyceric acid oxymethylene residue ( i.e. A in fig3 ). The R and S -glyceric acid oxymethylene residues represent an “opened” iduronic acid unit and an “opened” glucuronic acid unit, respectively, containing the essential carboxylate function in the appropriate configuration. The crucial step in the syntheses of these “opened” uronic acid pentamer analogues, was the preparation of the required glyceric acid oxymethylene residues 8a , 8b and 8c . Analogues II and III , containing an “opened” iduronic acid moiety, display a significant AT III mediated αXa activity. Compound III contains two extra sulphate groups at unit 2 . Removal of the contributing O-sulphate groups at position 3 and 6 of unit 6 of compound II ( i.e. compound IV ) results in a seven-fold drop in αXa activity. Replacement of the β-D-glucuronic acid unit by an S -glyceric acid oxymethylene residue ( i.e. compound V ) leads to almost a complete loss of αXa activity, notwithstanding the fact that all the essential and contributing charged groups are present in the molecule.

SAR study of 2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepines as progesterone receptor agonists.

We have developed a new class of progesterone receptor agonists having a tetracyclic dibenzo-oxazepine structure 1. In this paper, the synthesis and structure-activity relationships of this new class are described. This work led to the identification of potent progesterone agonists up to 1 nM activity. Substitution at positions 6, 7 and 1 has proven to be crucial for activity, indicating that probably these positions are involved in important interactions with the receptor.

1-aminoisoquinoline as benzamidine isoster in the design and synthesis of orally active thrombin inhibitors

Replacement of the highly basic benzamidine moiety of NAPAP by the moderately basic 1-aminoisoquinoline moiety resulted in thrombin inhibitors with improved selectivity towards trypsin and enhanced Caco-2 cell permeability.

Non-steroidal progesterone receptor modulators

The present invention provides compounds according to general Formula (I), a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of a prodrug thereof. More particularly, the present invention provides high affinity non-steroidal compounds which are agonists, partial agonists or antagonists of the progesterone receptor.Progesterone (P4) plays an essential role in female reproduction and progesterone receptor (PR) agonists have been used in female contraceptives and in postmenopausal hormone therapy. Recent studies in women and non-human primates show that PR antagonists may also have potential as contraceptive agents and for the treatment of various gynaecological and obstetric diseases, including fibroids, endometriosis and, possibly, hormone-dependent cancers. Clinically available PR agonists and antagonists are steroidal compounds and often cause various side effects due to their functional interaction with other steroid receptors. Recently, numerous receptor-selective non-steroidal PR agonists and antagonists have emerged. This patent review will focus on the latest developments in these areas (since 2000).

Novel acylguanidine containing thrombin inhibitors with reduced basicity at the P1 moiety

Replacement of the noragmatine group in thrombin inhibitors with a beta-alanyl-guanidine group resulted in a nearly equipotent and more selective compound 8 despite the fact that the pKa of this P1 moiety is five orders of magnitude lower. Further modification resulted in a nonpeptide inhibitor with this beta-alanyl-guanidine group, compound 28. This is an active and selective thrombin inhibitor and in view of its nonpeptide/low basicity structure selected for further pharmacological studies.

Design, synthesis and testing of amino-bicycloaryl based orally bioavailable thrombin inhibitors

Replacement of the highly basic benzamidine moiety with moderate basic amino-bicycloaryl moieties in a series of thrombin inhibitors related to NAPAMP provided potent enzyme inhibition and significant improvements in membrane transport and oral bioavailability.