Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit

Zbinden, Katrin Groebke; Anselm, Lilli; Banner, David W.; Benz, Jörg; Blasco, Francesca; Décoret, Guillaume; Himber, Jacques; Kuhn, Bernd; Panday, Narendra; Ricklin, Fabienne; Risch, Philippe; Schlatter, Daniel; Ståhl, Martin; Thomi, Stefan; Unger, R.; Haap, Wolfgang

doi:10.1016/j.ejmech.2008.12.025

Cited by 37 publications

(34 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The analogue with a difluoro-ethoxy substituent, exposing a weak hydrogen bond acceptor to the apolar protein region, binds considerably more strongly with a K i of 21 nM. (58)…”

Section: Resultsmentioning

confidence: 99%

Rationalizing Tight Ligand Binding through Cooperative Interaction Networks

Kuhn

Fuchs

Reutlinger

et al. 2011

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

Small modifications of the molecular structure of a ligand sometimes cause strong gains in binding affinity to a protein target, rendering a weakly active chemical series suddenly attractive for further optimization. Our goal in this study is to better rationalize and predict the occurrence of such interaction hot-spots in receptor binding sites. To this end, we introduce two new concepts into the computational description of molecular recognition. First, we take a broader view of noncovalent interactions and describe protein–ligand binding with a comprehensive set of favorable and unfavorable contact types, including for example halogen bonding and orthogonal multipolar interactions. Second, we go beyond the commonly used pairwise additive treatment of atomic interactions and use a small world network approach to describe how interactions are modulated by their environment. This approach allows us to capture local cooperativity effects and considerably improves the performance of a newly derived empirical scoring function, ScorpionScore. More importantly, however, we demonstrate how an intuitive visualization of key intermolecular interactions, interaction networks, and binding hot-spots supports the identification and rationalization of tight ligand binding.

show abstract

“…The analogue with a difluoro-ethoxy substituent, exposing a weak hydrogen bond acceptor to the apolar protein region, binds considerably more strongly with a K i of 21 nM. (58)…”

Section: Resultsmentioning

confidence: 99%

Rationalizing Tight Ligand Binding through Cooperative Interaction Networks

Kuhn

Fuchs

Reutlinger

et al. 2011

J. Chem. Inf. Model.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In their factor Xa (FXa) program, Zbinden et al added either a fluorine or hydroxyl group to a pyrrolidine ring in an attempt to improve metabolism ( Figure 3). 29 The RLM clearance of pyrrolidine analogue 6 was only slightly improved by adding a fluorine to the ring (analogue 7). However, when a hydroxyl group was added (8), the metabolic stability in RLM significantly improved probably because this compound was more polar than the other two.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

“…36 Another example where fluorine atoms were added to the piperidine ring was reported by Gleave et al (Figure 9). 37 In their cannabinoid receptor 2 (CB2) agonist program, they had tested the metabolic stability in RLM for a piperidine containing analogue (29) and its 4,4-difluoro derivative (30). There was very little improvement in the RLM metabolic stability for the 4,4-difluoro analogue.…”

Section: ■ Saturated Heterocyclesmentioning

confidence: 99%

Mitigating Heterocycle Metabolism in Drug Discovery

2012

View full text Add to dashboard Cite

In the past few decades, drug metabolism research has played an ever increasing role in the design of drugs. 1−3 In vitro metabolism assays 4 have become an integral part of the routine profiling of compounds made in drug discovery. 5 The data from these assays have allowed medicinal chemists to focus their efforts on compounds with improved metabolic stability. 6 Detailed metabolite identification studies are also done more routinely, which provide information on how to strategically replace or block metabolically labile sites. 7 Additionally, in vivo PK studies are regularly conducted in drug discovery, which helps to build in vitro−in vivo PK relationships. 4 The positive influence that these advances in PKDM sciences have had on drug discovery is reflected in the fact that fewer drug candidates fail in the clinic for PKDM related issues. 8 This suggests that medicinal chemists are successfully integrating the data generated by their PKDM colleagues into the design of compounds with fewer metabolic liabilities.Extensive data from metabolism studies have allowed medicinal chemists to develop general principles for reducing compound metabolism. These methods include, but are not limited to, reducing lipophilicity, altering sterics and electronics, introducing a conformational constraint, and altering the stereochemistry of their compounds. While no single method is able to solve every metabolic problem, these principles do give medicinal chemists guidance on how to improve the metabolic liabilities of their compounds. If the specific site of metabolism is known, medicinal chemists block the site, typically with a fluorine, or replace the metabolically labile group with a bioisostere. 9 While several authors have reviewed these techniques for reducing metabolism, 5,10,11 there is no review that summarizes different approaches to improving the metabolic stability of heterocycles. In this review, we summarize examples where changes were made at or near the heterocycle to improve metabolic stability. By summarizing these examples, we hope to provide a useful guide to medicinal chemists as they attempt to improve the metabolic profile of their own heterocyclic compounds.The majority of the examples that are included in this review came from searching the online open access database CHEMBL. 12 In addition to having pharmacology data on compounds from the medicinal chemistry literature, CHEMBL has over 120 000 points of data on the ADMET properties of compounds. With the help of the visualization software Spotfire, we were able to cull examples from the CHEMBL ADMET data that focused on heterocycles. We also identified examples from papers that cite leading reviews in the drug metabolism field 13−18 and were present in other recent reviews on drug metabolism. 19−22 The main criteria that we placed on the examples selected for this review was that the change made to improve metabolism had to occur at or near the heterocycle and nowhere else on the molecule. This allowed us to eliminate examples where a change made t...

show abstract

“…Few of the compounds in this library have the frequently observed basic amino functionality such as the benzamidine of SK549. The co-crystallized ligand, 1, was reported to have a Ki of 6 nM [31] and had a glide score of -9.17 in our docking model. This is comparable to the best Glide score found, -9.25, for compound 11{4,21}.…”

Section: Synthesis Of Scaffolds and Library Preparationmentioning

confidence: 99%

Design and Synthesis of 3-Arylisoxazoline-5-Carboxamide and 3-Arylisoxazoline-5-Acetamide Libraries as Potential Factor Xa Inhibitors

Quinn¹,

Gregg²,

Kitchen³

et al. 2012

LDDD

View full text Add to dashboard Cite

Two synthetic libraries based on a core isoxazoline motif have been designed and prepared specifically to probe the S1 and S4 binding pockets of the Factor Xa enzyme active sites. A highly efficient parallel solution phase synthetic method resulted in the synthesis of 3-arylisoxazoline-5-carboxamides and 3-arylisoxazoline-5-acetamides libraries yielding 192 compounds in total. Highlights of this work include preparation of the isoxazoline cores via a [3+2] cycloaddition between oximes with acrylates or vinyl acetates and the use of activated p-nitrophenyl esters for ease of amide formation and reaction purification.

show abstract

Design of novel aminopyrrolidine factor Xa inhibitors from a screening hit

Cited by 37 publications

References 35 publications

Rationalizing Tight Ligand Binding through Cooperative Interaction Networks

Rationalizing Tight Ligand Binding through Cooperative Interaction Networks

Mitigating Heterocycle Metabolism in Drug Discovery

Design and Synthesis of 3-Arylisoxazoline-5-Carboxamide and 3-Arylisoxazoline-5-Acetamide Libraries as Potential Factor Xa Inhibitors

Contact Info

Product

Resources

About