Ingemar Nilsson

A new oral anticoagulant: the 50-year challenge

It is rare for any drug introduced more than 50 years ago to remain unsurpassed today; yet the oral prevention and treatment of thrombosis are still achieved by the use of the vitamin K antagonists (coumarins), such as warfarin, which were introduced in the 1940s and 1950s. For these anticoagulants, careful monitoring of the effect is needed to avoid bleeding or loss of efficacy. On the basis of the need for improved oral anticoagulants, a goal was set in 1985 to develop a new oral anticoagulant that could replace the vitamin K antagonists. After providing some medical and historical context, this article discusses the challenges facing the multidisciplinary team of scientists who were involved in the project leading to the discovery of the anticoagulant ximelagatran (Exanta; AstraZeneca), the first oral direct thrombin inhibitor.

Investigation of the relationship between topology and selectivity for druglike molecules.

There is a strong interest in drug discovery and development to advance the understanding of pharmacological promiscuity. Improved understanding of how a molecular structure is related to promiscuity could help to reduce the attrition of compounds in the drug discovery process. For this purpose, a descriptor is introduced that describes the structural complexity of a compound based on the size of its molecular framework (MF) in relation to its overall size. It is defined as the fraction of the size of the molecular framework versus the size of the whole molecule (f(MF)). It is demonstrated that promiscuity correlates with f(MF) for large f(MF) values. The observed correlation is not due to lipophilicity. To provide further explanation of this observation, it was found that the number of terminal ring systems in a compound is correlated with promiscuity. The analysis presented here might help medicinal chemists to improve the selectivity for compounds in drug discovery projects.

Targeting thrombin and factor VIIa: design, synthesis, and inhibitory activity of functionally relevant indolizidinones

Guided by molecular modeling, docking experiments, and available X-ray crystal structure data on the serine protease Factor VIIa and thrombin, a series of indolizidinone derivatives was designed and synthesized having diverse functionality at the P1, P2, and P3 sites.

Exploring the chiral space within the active site of α-thrombin with a constrained mimic of d-Phe-Pro-Arg — design, synthesis, inhibitory activity, and X-ray structure of an enzyme–inhibitor complex

An indolizidinone motif with strategically placed substitutents was designed and synthesized as a constrained mimic of D-Phe-Pro-Arg. Low nanomolar inhibition of alpha-thrombin validates the design elements in this inhibitor which also exhibits a 20-fold selectivity for thrombin versus trypsin. An X-ray crystal structure of the inhibitor with alpha-thrombin shows the expected interactions with key amino acids within the active site and some notable changes in positions.

Beyond the Scope of Free-Wilson Analysis: Building Interpretable QSAR Models with Machine Learning Algorithms

A novel methodology was developed to build Free-Wilson like local QSAR models by combining R-group signatures and the SVM algorithm. Unlike Free-Wilson analysis this method is able to make predictions for compounds with R-groups not present in a training set. Eleven public data sets were chosen as test cases for comparing the performance of our new method with several other traditional modeling strategies, including Free-Wilson analysis. Our results show that the R-group signature SVM models achieve better prediction accuracy compared with Free-Wilson analysis in general. Moreover, the predictions of R-group signature models are also comparable to the models using ECFP6 fingerprints and signatures for the whole compound. Most importantly, R-group contributions to the SVM model can be obtained by calculating the gradient for R-group signatures. For most of the studied data sets, a significant correlation with that of a corresponding Free-Wilson analysis is shown. These results suggest that the R-group contribution can be used to interpret bioactivity data and highlight that the R-group signature based SVM modeling method is as interpretable as Free-Wilson analysis. Hence the signature SVM model can be a useful modeling tool for any drug discovery project.

Parallel solution phase synthesis of N-substituted 2-pyrazoline libraries

The value of α,β-unsaturated ketones (chalcones) as templates for the combinatorial assembly of N-substituted 2-pyrazolines has been explored. Based on a set of 80 chalcones, an array of 1500 N-carbamoyl, carbonyl and sulfonyl pyrazolines were produced demonstrating that a broad range of diversity can be fabricated around the pyrazoline motif. The efficient utilization of polymer-supported reagents and scavengers aided in providing typical purities of 75–98%.

Design, synthesis, and thrombin-inhibitory activity of pyridin-2-ones as P2/P3 core motifs.

Guided by available X-ray crystal structure data on the serine protease thrombin, a series of pyridin-2-one derivatives were designed and synthesized having diverse functionality at the P(1) and P(3) sites. Potent in vitro activity against thrombin, with excellent selectivity over trypsin was found for selected analogues.

Creating Novel Activated Factor Xi Inhibitors Through Fragment Based Lead Generation and Structure Aided Drug Design.

Activated factor XI (FXIa) inhibitors are anticipated to combine anticoagulant and profibrinolytic effects with a low bleeding risk. This motivated a structure aided fragment based lead generation campaign to create novel FXIa inhibitor leads. A virtual screen, based on docking experiments, was performed to generate a FXIa targeted fragment library for an NMR screen that resulted in the identification of fragments binding in the FXIa S1 binding pocket. The neutral 6-chloro-3,4-dihydro-1H-quinolin-2-one and the weakly basic quinolin-2-amine structures are novel FXIa P1 fragments. The expansion of these fragments towards the FXIa prime side binding sites was aided by solving the X-ray structures of reported FXIa inhibitors that we found to bind in the S1-S1’-S2’ FXIa binding pockets. Combining the X-ray structure information from the identified S1 binding 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment and the S1-S1’-S2’ binding reference compounds enabled structure guided linking and expansion work to achieve one of the most potent and selective FXIa inhibitors reported to date, compound 13, with a FXIa IC50 of 1.0 nM. The hydrophilicity and large polar surface area of the potent S1-S1’-S2’ binding FXIa inhibitors compromised permeability. Initial work to expand the 6-chloro-3,4-dihydro-1H-quinolin-2-one fragment towards the prime side to yield molecules with less hydrophilicity shows promise to afford potent, selective and orally bioavailable compounds.

Stereocontrolled synthesis of enantiopure diversely functionalized prototypical piperidinone libraries, and constrained analogs of 4-substituted 2-amino adipic acid

Enantiopure 2-substituted 4,5-unsaturated piperidinones were subjected to stereocontrolled nitroalkane additions and the corresponding products were further manipulated to produce 4-aminomethyl derivatives. Diverse substitution led to a set of 4-arylsulfonamides and O-carbamates as examples of prototypical piperidinone libraries with two sites of diversity.

Stereocontrolled synthesis of a prototype library of enantiopure 2,4-disubstituted 4-aryl-6-piperidinones and piperidines

Addition of a set of aryl cuprates to N-Boc O-TBDPS 2-hydroxymethyl 3,4-unsaturated 6-piperidinones affords syn-adducts in preference to anti when mixed Grignard-cuprates are used. Aryllithio cuprates give more of the anti-isomer in some cases. A library of 2-hydroxymethyl carbamates (27 compounds) and 2-hydroxymethyl aryl ethers and thioethers (19 compounds) was generated from a selection of 4-aryl-6-piperidinones, and some were further reduced to the corresponding piperidines (9 compounds).