Anton Egbert Peter Adang

The First Orally Active Low Molecular Weight Agonists for the LH Receptor: Thienopyr(im)idines with Therapeutic Potential for Ovulation Induction

The gonadotropins, a class of glycoproteins with an average molecular weight of 30 kD, play a pivotal role in human reproduction. Follicle stimulating hormone (FSH), for example, causes ovarian follicle maturation in women and is involved in spermatogenesis in men. Luteinizing hormone (LH) is responsible for ovulation induction in women and controls testosterone production in men. Finally, human choriogonadotropin (hCG) maintains the early stages of a pregnancy. All gonadotropins consist of a common subunit and a hormone-specific Support from the Forschungsinstitut f ̧r Molekulare Pharmakologie is gratefully acknowledged. M.S. was supported by the DFG Graduiertenkolleg GRK 80 TMModellstudien∫. The authors thank Wolfgang Bermel for helpful discussions regarding the setup of the TROSY experiments, Hartmut Oschkinat for his continuous encouragement, and Karen Zierler for carefully reading the manuscript.

The contribution of combinatorial chemistry to lead generation: an interim analysis.

In the process of finding new drug candidates medicinal chemists nowadays have a variety of options to choose from, one is to apply combinatorial chemistry techniques. Since the early 1990s synthetic and analytical methods as well as new technologies have been growing rapidly in the area of combinatorial chemistry. Applying these techniques have resulted in the production of large numbers of compounds. A trend is observed towards smaller libraries of compounds with more drug-like properties. An analysis is made to establish the contribution of combinatorial chemistry in providing new lead candidates for (pre)clinical development towards new pharmaceutical products. Ten representative examples are given to describe the impact of ombinatorial chemistry on different levels of the lead discovery and optimization process. Furthermore, reports on combinatorial chemistry products that are already in (pre)clinical development were traced back to their source. The interim analysis showed only limited success of combinatorial chemistry approaches in terms of delivering leads. Second generation libraries appear more drug-like and focussed and may result in more compounds entering clinical studies in the future.

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.

Solution-phase and solid-phase synthesis of novel transition state inhibitors of coagulation enzymes incorporating a piperidinyl moiety

2-Amino-3-piperidin-4-yl-propionic acid containing peptidomimetics are potent protease inhibitors when combined with an appropriate keto-thiazole or keto-carboxylic acid moiety. A novel P1 residue in factor Xa and thrombin inhibitors has been found resulting in IC50 values as low as 0.048 microM, a factor of ten more potent than Argatroban. Starting with non-chiral synthetic routes, a new stereospecific route was developed as well as a new solid-phase method.