Efficient asymmetric synthesis of ABT-594; a potent, orally effective analgesic

Lynch, John K.; Holladay, Mark W.; Ryther, Keith B.; Bai, Hao; Hsiao, Chi-Nung; Morton, Howard E.; Dickman, Daniel A.; Arnold, William H.; King, Steven A.

doi:10.1016/s0957-4166(98)00291-2

Cited by 39 publications

(28 citation statements)

References 16 publications

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“…During our lead optimization campaign, however, the hydrochloride or trifluoroacetate salts of compound 3 or 4 were found to be hygroscopic and gradually decomposed to form a dimer of the parent structure. This was consistent with the literature findings in the case of the related compound ABT-594 ( 5 ), which was reported to dimerize to compound 6 in the presence of HCl or TFA following exposure to water[12]. Synthetic efforts were thus made to overcome this issue by utilizing an N -methylpyrrolidine or diazabicyclo[3.3.0]octane moiety to replace the azetidine group present in compound 3 [13, 14].…”

Section: Introductionsupporting

confidence: 85%

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Zhang

Eaton

Fedolak

et al. 2016

European Journal of Medicinal Chemistry

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We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Ki values of 0.5–51.4 nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50 and IC50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86Rb+ ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube® platform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.

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Section: Introductionsupporting

confidence: 85%

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Zhang

Eaton

Fedolak

et al. 2016

European Journal of Medicinal Chemistry

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“…Similar intermolecular dimerization was also observed by Abbott chemists during the process of salt screening and selection for compound 1 . 17 Although this potential stability issue can be prevented by changing the salt form of these azetidine-containing ligands, 17 replacement of the azetidine unit by other ring systems having improved chemical stability is a logical first choice. Thus, in continuation of our efforts to develop α4β2-nAChR ligands for treating depression, a novel series of nAChR ligands with different ring systems replacing the azetidine ring found in the lead compound 4 were designed and synthesized for pharmacological evaluation.…”

Section: Introductionmentioning

confidence: 99%

Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II

Zhang

Eaton

et al. 2013

J. Med. Chem.

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A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds 24, 26, and 30 demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.

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“…It is notable that the azetidine in 11 (Table 4 ) did not undergo ring opening, a competing reaction observed under acidic conditions. 15 …”

Section: Resultsmentioning

confidence: 99%

Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

2014

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We report the late-stage functionalization of multisubstituted pyridines and diazines at the position α to nitrogen. By this process, a series of functional groups and substituents bound to the ring through nitrogen, oxygen, sulfur, or carbon are installed. This functionalization is accomplished by a combination of fluorination and nucleophilic aromatic substitution of the installed fluoride. A diverse array of functionalities can be installed because of the mild reaction conditions revealed for nucleophilic aromatic substitutions (SNAr) of the 2-fluoroheteroarenes. An evaluation of the rates for substitution versus the rates for competitive processes provides a framework for planning this functionalization sequence. This process is illustrated by the modification of a series of medicinally important compounds, as well as the increase in efficiency of synthesis of several existing pharmaceuticals.

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Efficient asymmetric synthesis of ABT-594; a potent, orally effective analgesic

Cited by 39 publications

References 16 publications

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

Chemistry, Pharmacology, and Behavioral Studies Identify Chiral Cyclopropanes as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists Exhibiting an Antidepressant Profile. Part II

Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution

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