General and Mild Preparation of 2-Aminopyridines

Londregan, Allyn T.; Jennings, Sandra; Wei, Liuqing

doi:10.1021/ol102301u

Cited by 141 publications

(87 citation statements)

References 18 publications

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“…18 On the other hand, α-methyl substitution (26) and β,β-dimethyl substitution (23) almost completely abolished the inhibitory effect of c8 (for further comparison, see Supporting Information). 7 While most N-arylsulfonyl-L-proline headgroup modifications failed to increase the potency, we did observe that piperidine replacement (18,19) showed slightly higher potency than c8. We speculate that pyrrolidine and piperidine share similar position conformations to locate the hydrophobic phenyl ring into the hydrophobic pocket (Figure 4).…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 62%

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

Reed

Tang

McIntosh

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure−activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-L-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics.KEYWORDS: Fibrosis, αvβ1 integrin, phenylsulfonylproline, TGFβ, integrin antagonist I ntegrins are transmembrane proteins that mediate cell−cell and cell−extracellular matrix (ECM) interactions.1 They exist as heterodimeric proteins consisting of an alpha (α) and beta (β) subunit. Multiple isoforms of each subunit have been identified so far with more than half of the integrins containing either the alpha v (αv) or beta 1 (β1) subunit.2 Due to their crucial biological roles in cell adhesion and proliferation, integrins have been extensively studied as therapeutic targets in cardiovascular diseases as well as cancer chemotherapy, and a few integrin inhibitors have reached the clinic.3 Integrins are also involved in the activation of TGFβ, a key cytokine in fibrotic diseases. An antibody against the epithelium-specific αvβ6 integrin (STX-100) is in phase II clinical trials for idiopathic pulmonay fibrosis (IPF). 4 We recently identified a role for another integrin, αvβ1, in activating TGFβ to drive organ fibrosis.5,6 A prototype inhibitor, c8, significantly reduced the fibrotic markers in mouse model for liver and lung fibrosis (Figure 1). These findings suggest that inhibitors of αvβ1 integrin could be promising new antifibrotic agents. However, αvβ1 integrin has not been widely studied, and little structural information on αvβ1 integrin is known. To our knowledge, no other selective and potent αvβ1 integrin inhibitors have been developed so far. Thus, we turned our attention to developing antifibrotic agents based upon modification of c8. Structurally, c8 (and its congener c6) mimics the natural ligand tripeptide sequence Arg-Gly-Asp (RGD) by connecting carboxylic acid and guanidinine through a linker. c8 also contains Narylsulfonyl-L-proline scaffold previously shown to confer specificity and potency in inhibition of other β1 integrins (α2β1 and α4β1). 7−10Based upon this analysis, we first investigated how the structural modification in N-arylsulfonyl-L-prolyl group would influence the potency (Figure 2). It was previously shown that a number of aryl or prolyl analogues in the same N-arylsulfonyl-Lprolyl scaffold were identified as potent non-RGD β1 integrin inhibitors. 8,9,11 However, it remains unclear if it holds true in the case of RGD integrin inhibitors like c8. Second, we were

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 62%

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

Reed

Tang

McIntosh

et al. 2016

ACS Med. Chem. Lett.

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“…This is not surprising in light of the observation that “hard” nucleophiles (e. g. nitrogen nucleophiles) tend to attack alkylpyridinium salts primarily at the 2-position via a charge-controlled (polar) mechanism. 35 While most of the sulfonic acid-derived activators led to a small amount of 1a′ due to cyclization at the 4-position (entries 1 – 3), the use of trifluoroacetic anhydride (TFAA, entry 4) and the peptide coupling agent bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, entry 5) 32 completely abolished the formation of 1a′ . The use of acetic anhydride (entry 7) proved problematic.…”

Section: Resultsmentioning

confidence: 99%

“…13,24–27 One possible way to eliminate this requirement is to take advantage of the electrophilic 2-position of a suitably activated pyridine N -oxide using a strategy (Scheme 2) similar to the Reissert-Henze reaction, 28 an approach which has been employed in the preparation of 2-aminopyridines 29–32 via intermolecular amination of pyridine N -oxide, and also has recently been used to functionalize the 2-position of pyridine through the N -oxide with oxygen, sulfur and carbon nucleophiles. 33 Since the introduction of a halogen to the 2-position of pyridine typically requires prior formation of the N -oxide, 13 this method would also eliminate a step in the formation of 1 and thus be a more efficient route to these compounds.…”

Section: Introductionmentioning

confidence: 99%

Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by ring closure of 3-acylpyridine N-oxide tosylhydrazones

Lominac

D’Angelo

Smith

et al. 2012

Tetrahedron Letters

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3-Acylpyridine N-oxide tosylhydrazones give good overall yields of a mixture of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines when treated with an electrophilic additive and an amine base. (Z)-Hydrazones cyclize readily, while (E)-hydrazones fail to react under the reported conditions. The reaction takes place at room temperature, and moderate regiocontrol over the cyclization can be achieved by varying the electrophile/solvent combination.

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“…In this reaction, unhinderedaliphatic amines participated most effectively in the transformation, but aminations using heterocycles, such as imidazoles and pyrazoles, unexpectedly proceeded (Scheme 10). 16 The mechanism of the reaction is shown in Scheme 11. The reaction proceeded via the activated pyridine complex 24.…”

Section: Methodsmentioning

confidence: 99%

Synthesis of 2-substituted pyridines from pyridine N-oxides

Liu¹,

Luo²,

Xu³

et al. 2013

Arkivoc

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The synthesis of substituted pyridines has drawn the attention of many chemists due to their importance as building blocks for biologically active compounds and materials. This mini-review focuses on recent developments relating to the synthesis of substituted pyridines from pyridine N-oxides, along with their interesting mechanism aspects. New developments including alkenylation, alkynylation, alkylation, arylation, amination and cyanation are discussed.

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General and Mild Preparation of 2-Aminopyridines

Cited by 141 publications

References 18 publications

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

Construction of pyrazolo[3,4-b]pyridines and pyrazolo[4,3-c]pyridines by ring closure of 3-acylpyridine N-oxide tosylhydrazones

Synthesis of 2-substituted pyridines from pyridine N-oxides

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