A practical drug discovery project at the undergraduate level.

In this article, we describe a practical drug discovery project for third-year undergraduates. No previous knowledge of medicinal chemistry is assumed. Initial lecture workshops cover the basic principles; then students, in teams, seek to improve the profile of a weakly potent, insoluble phosphatidylinositide 3-kinase delta (PI3Kδ) inhibitor (1) through compound array design, molecular modelling, screening data analysis and the synthesis of target compounds in the laboratory. The project benefits from significant industrial support, including lectures, student mentoring and consumables. The aim is to make the learning experience as close as possible to real-life industrial situations. In total, 48 target compounds were prepared, the best of which (5b, 5j, 6b and 6ap) improved the potency and aqueous solubility of the lead compound (1) by 100-1000 fold and ≥tenfold, respectively.

Structure and property based design of factor Xa inhibitors: biaryl pyrrolidin-2-ones incorporating basic heterocyclic motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating basic biaryl P4 groups, producing highly potent inhibitors with significant anticoagulant activities and encouraging oral pharmacokinetic profiles.

Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with biaryl P4 motifs.

Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating biaryl P4 groups, producing highly potent inhibitors with encouraging oral pharmacokinetic profiles and significant but sub-optimal anticoagulant activities.

Selective and dual action orally active inhibitors of thrombin and factor Xa.

The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.

Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.

Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.

Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.

Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.

Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.

A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.