There remains a high unmet medical need for a safe oral therapy for thrombotic disorders. The serine protease factor Xa (fXa), with its central role in the coagulation cascade, is among the more promising targets for anticoagulant therapy and has been the subject of intensive drug discovery efforts. Investigation of a hit from high-throughput screening identified a series of thiophene-substituted anthranilamides as potent nonamidine fXa inhibitors. Lead optimization by incorporation of hydrophilic groups led to the discovery of compounds with picomolar inhibitory potency and micromolar in vitro anticoagulant activity. Based on their high potency, selectivity, oral pharmacokinetics, and efficacy in a rat venous stasis model of thrombosis, compounds ZK 814048 (10b), ZK 810388 (13a), and ZK 813039 (17m) were advanced into development.

HTS screening identified 1 with micromolar inhibitory activity against PDK1. Optimization of 1 afforded 4i (BX-517) which has single-digit nanomolar activity against PDK1 and excellent selectivity against PKA.

High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.

The Pictet-Spengler cyclization utilizing tryptophan linked to the Kaiser oxime resin and aldehydes affords the 1,2,3,4-tetrahydro-β-carboline derivatives 6 which can be further functionalized by reaction with acylating reagents. Nucleophilic cleavage with amines affords the final products 7 in high yield and purity.

With this minireview, concepts about how c-AMP and various inhibitor molecules interact with the phosphodiesterases seem to have come full-circle. It will be proposed and elaborated herein that an understanding of SAR for the newest, “second generation” PDE inhibitors is best accomplished by adopting a model that supposes that these compounds are transition state inhibitors. The analysis finds an interesting parallel with early studies where it was recognized that c-AMP adopts a trigonal bipyramid transition state during hydrolysis. The dynamic interaction of ligands with the phosphodiesterase enzymes will also be made evident when simple algebraic expressions are shown to be inadequate for predicting inhibitor potencies. The latter are apparently complicated by cooperative or synergistic relationships that occur among the various binding sites within the receptor. Finally, implications that can be derived from certain topographical features of the model are discussed relative to a range of potential therapeutic indications.