Design and Synthesis of Pyrrolidine-based Fragments That Sample Three-dimensional Molecular Space

Garner, Philip; Cox, Philip B.; Rathnayake, Upendra A.; Holloran, Nicholas; Erdman, Paul

doi:10.1021/acsmedchemlett.9b00070

Cited by 30 publications

(22 citation statements)

References 21 publications

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“…Besides the aforementioned utility of the NH ‐2‐pyrrolidone motif in medicinal chemistry, compounds 3 can be viewed as starting materials for 3‐substituted pyrrolidines, one of the most commonly used amines in medicinal chemistry . To illustrate this possibility, a small set of NH ‐2‐pyrrolidones 3 was reduced with LAH in refluxing THF to give pyrrolidines 7a – d in good to excellent yields (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

2020

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tert-Butyl 3-diazo-2-oxopyrrolidine-1-carboxylate synthesized on multigram scale has been employed to introduce a privileged NH-2-pyrrolidone moiety via oxygen, sulfur[a] Saint 3013 and nitrogen atom to partner molecules via Rh II -catalyzed X-H insertion followed by Boc group removal. Further manipulation of pyrrolidine moiety has been exemplified. periphery element -endows the resulting compounds with diverse biological activities as the result of affinity to respective protein targets. [1] Besides approved drugs based on 2-pyrrolidone as a scaffold (e.g., natural metabolite of nicotine, antidepressant cotinine, [2] respiratory stimulant doxapram, [3] nootropic and cognition-modulating drug piracetam [4] and antiseizure ethosuximide [5] ), there is a wealth of bioactive molecules featured in the recent patent literature which contains an N-unsubstituted ("NH-") 2-pyrrolidone moiety as an element of molecular periphery, linked via a bond between C-3 and a heteroatom (mostly nitrogen, less frequently oxygen or sulfur). Relevant examples, include Bruton's tyrosine kinase inhibitor Full Paper 1, [6] inhibitor of respiratory syncytial virus (RSV) 2, [7] Syngenta's fungicide 3, [8] immunomodulating inhibitor of IL-17 4, [9] hepatitis B virus capsid assembly modulator 5, [10] adenosine receptor modulator 6, [11] ghrelin O-acyl transferase (GOAT) inhibitor 7 for treatment of diabetes and obesity, [12] ubiquitin-specific processing protease 7 (USP7) inhibitor 8 for cancer treatment [13] and cannabinoid receptor hCB2 agonist 9 [14] (Figure 1).From drug design prospective, the advantages of using NH-2-pyrrolidone are quite intuitive as this polar (cLog P = -0.18 [15] ) motif contains a hydrogen-bond donor/acceptor pair capable of building cooperative interactions with protein backbone, would likely improve drug candidate's aqueous solubility and will not reflect negatively on the molecule's degree of saturation (F sp3 ), a routinely observed parameter in modern drug discovery. [16,17] The primary means of introducing the NH-2-pyrrolidone moiety is via the use of either 3-amino-2-pyrrolidone or 3-bromo-2-pyrrolidone. Recently, we have been investigating synthesis and Rh II -catalyzed X-H insertion reactions of a novel type of α-diazocarbonyl compounds -α-diazo-γ-lactams 1. [18][19][20] The primary limitation of this chemistry was identified with respect to the substituents on the lactam nitrogen atom: the diazo compounds were stable to isolation and use in subsequent transformation only for N-aryl lactams, i.e. when the nitrogen lone pair is delocalized thereby increasing the electron-withdrawing character of the aminocarbonyl moiety. In contrast, N-alkyl derivatives (as well as o-substituted aromatic groups incapable of effective conjugation for steric reasons) are unstable due to nitrogen-extrusive dimerization [18] and can only be used in situ, as soon as they have been obtained. [21] We reasoned that if an alkoxycarbonyl-type protecting group (e.g., Boc as in 2) was placed on the nitrogen atom of α-diazo-γ-lactam core...

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Section: Resultsmentioning

confidence: 99%

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

2020

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“…Due to drugs and chemical probes having a high degree of 3D character, 3D-enriched fragment libraries are increasingly being explored to generate starting chemical matter for inhibitor development [ 8 , 12 , 15 , 57 , 58 , 59 , 60 ]. The main concerns with using 3D-enriched fragments are the potential for lower hit rates due to increased complexity and hits that are biased away from fragments with 3D character limiting the utility of using these higher complexity molecules.…”

Section: Discussionmentioning

confidence: 99%

Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains

et al. 2020

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As fragment-based drug discovery has become mainstream, there has been an increase in various screening methodologies. Protein-observed 19F (PrOF) NMR and 1H CPMG NMR are two fragment screening assays that have complementary advantages. Here, we sought to combine these two NMR-based assays into a new screening workflow. This combination of protein- and ligand-observed experiments allows for a time- and resource-efficient multiplexed screen of mixtures of fragments and proteins. PrOF NMR is first used to screen mixtures against two proteins. Hit mixtures for each protein are identified then deconvoluted using 1H CPMG NMR. We demonstrate the benefit of this fragment screening method by conducting the first reported fragment screens against the bromodomains of BPTF and Plasmodium falciparum (Pf) GCN5 using 467 3D-enriched fragments. The hit rates were 6%, 5% and 4% for fragments binding BPTF, PfGCN5, and fragments binding both proteins, respectively. Select hits were characterized, revealing a broad range of affinities from low µM to mM dissociation constants. Follow-up experiments supported a low-affinity second binding site on PfGCN5. This approach can be used to bias fragment screens towards more selective hits at the onset of inhibitor development in a resource- and time-efficient manner.

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“…This is similar to pyrrolidines which are common scaffolds in drugs and known to enhance the 3D nature of fragments, with enabling chemistries employed to maximize both 2 and especially 3D diversity of fragment space. 15 It is interesting to note that the unsubstituted methanoproline intermediates are highly saturated with proportionate levels of Fsp 3 , however for the majority of the corresponding substituted amide products, the level of 3 dimensionality increases as the level of saturation decreases. As an example, we analysed the series of compounds from the methanoprolinol derivative (compound 7) and plotted Fsp 3 versus PBF score.…”

Section: Computational Analysismentioning

confidence: 99%

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character

Cox

Zdorichenko

Cox

et al. 2020

ACS Med. Chem. Lett.

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Design and Synthesis of Pyrrolidine-based Fragments That Sample Three-dimensional Molecular Space

Cited by 30 publications

References 21 publications

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character

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Design and Synthesis of Pyrrolidine-based Fragments That Sample Three-dimensional Molecular Space

Cited by 30 publications

References 21 publications

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via RhII‐Catalyzed X–H Insertion Reactions

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via RhII‐Catalyzed X–H Insertion Reactions

Combined Protein- and Ligand-Observed NMR Workflow to Screen Fragment Cocktails against Multiple Proteins: A Case Study Using Bromodomains

Escaping from Flatland: Substituted Bridged Pyrrolidine Fragments with Inherent Three-Dimensional Character

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tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions

tert‐Butyl 3‐Diazo‐2‐oxopyrrolidine‐1‐carboxylate – A New Reagent for Introduction of the 2‐Oxopyrrolidin‐3‐yl Motif via Rh^II‐Catalyzed X–H Insertion Reactions