Structural Analysis and Optimization of NK<sub>1</sub> Receptor Antagonists through Modulation of Atropisomer Interconversion Properties

Albert, Jeffrey S.; Ohnmacht, Cyrus J.; Bernstein, Peter R; Rumsey, William L.; Aharony, David; Alelyunas, Yun W.; Russell, Daniel; Potts, William; Sherwood, Scott; Shen, Lihong; Dedinas, Robert F.; Palmer, William E.; Russell, Keith

doi:10.1021/jm030197g

Cited by 28 publications

(9 citation statements)

References 41 publications

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“…1d/1b, 1b/1a, 1a/1c, and 1c/1d) was not seen. 10 Such behavior has been observed for related naphthamide systems. 11 In these cases, it is understood that the fastest interconversions are due to the simultaneous, paired rotation of the naphthamide -aryl and amide bonds.…”

Section: Introductionsupporting

confidence: 56%

“…13 The long rotational half-life (approximately 1.8 days at 37 8C) allowed us to individually test each component of 1. 10 We found that most of the in vivo NK 1 activity was associated with the single atropisomer, 1d. Using a combination of kinetic and spectroscopic studies, we assigned structures for each of the atropisomers as indicated in Figure 3.…”

Section: Introductionmentioning

confidence: 74%

“…Using a combination of kinetic and spectroscopic studies, we assigned structures for each of the atropisomers as indicated in Figure 3. 10 Based on the structural model for 1d, we reasoned that we could enforce the single, desired conformation by introducing a tether to connect the methyl group of the amide with the naphthalene 2-position. Such a tether should stabilize the NK 1 binding conformation because the amide would be locked in the trans configuration.…”

Section: Introductionmentioning

confidence: 99%

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Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

et al. 2004

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Section: Introductionsupporting

confidence: 56%

Section: Introductionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

et al. 2004

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“…Therefore, historically, equilibration between conformers was rarely considered as impacting nucleation and crystallization kinetics [50]. However, there is steady growing evidence that improved potency of specific conformers under physiological conditions led to an increase in the focus on relatively stable conformers, as evidenced by recent reports [51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68]. Since crystallization is the main purification and separation unit operation in the development of new medicines, studies about molecular flexibility and the effect of the presence of conformation stability and conversion in solution on nucleation, crystal growth and polymorphism has also been steadily increasing [50,[69][70][71][72][73][74][75][76][77][78][79][80][81][82].…”

mentioning

confidence: 99%

Review and Modeling of Crystal Growth of Atropisomers from Solutions

2019

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In this paper, theories on anisotropic crystal growth and crystallization of atropisomers are reviewed and a model for anisotropic crystal growth from solution containing slow inter-converting conformers is presented. The model applies to systems with growth-dominated crystallization from solutions and assumes that only one conformation participates in the solute integration step and is present in the crystal lattice. Other conformers, defined as the wrong conformers, must convert to the right conformer before they can assemble to the crystal lattice. The model presents a simple implicit method for evaluating the growth inhibition effect by the wrong conformers. The crystal growth model applies to anisotropic growth in two main directions, namely a slow-growing face and a fast-growing face and requires the knowledge of solute crystal face integration coefficients in both directions. A parameter estimation algorithm was derived to extract those coefficients from data about temporal concentration and crystal size during crystallization and was designed to have a short run time, while providing a high-resolution estimation. The model predicts a size-dependent growth rate and simulations indicated that for a given seed size and solvent system and for an isothermal anti-solvent addition crystallization, the seed loading and the supersaturation at seeding are the main factors impacting the final aspect ratio. The model predicts a decrease of the growth inhibition effect by the wrong conformer with increasing temperature, likely due to faster equilibration between conformers and/or a decrease of the population of the wrong conformer, if of low energy, at elevated temperatures. Finally, the model predicts that solute surface integration becomes the rate-limiting mechanism for high solute integration activation energies, resulting in no impact of the WC on the overall crystal growth process.

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“…The naphthyl amide organic fragment is prevalent in a number of bioactive compounds [1][2][3][4][5][6] including those targeting the NK1 receptor, 1 the inhibition of aldosterone synthase, 3 the leukocyte proteases cathepsin G 4 and chymase, 5 and a malarial receptor. 2 Aromatic amides including some naphthyl amides are also central to the inhibition of a group of poly(ADP-ribose) polymerase enzymes (PARPs) [7][8][9] that bind NAD + and have been implicated in the cellular response to DNA injury.…”

mentioning

confidence: 99%

A BF₃-Mediated Nitrogen-to-Carbon Rearrangement of N-Protected 2,3-Dihydro-3-hydroxy-1H-benzisoindol-1-ones, and Its Interception for a Facile Preparation of 3-Substituted Benzisoindolones

Schwan¹,

Duspara²,

Paquette³

et al. 2006

Synlett

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R e a r r a n g e m e n t o f N -P r o t e c t e d 2 , 3 -D i h y d r o -3 -h y d r o x y -1 H -b e n z i s o i n d o l -1 -o n e sAbstract: A BF 3 -mediated release of the hydroxy and the nitrogenprotecting group of N-(cumyl or 1,1-diphenylethyl)-2,3-dihydro-3-hydroxy-1H-benzisoindol-1-ones is accompanied by recombination of the nitrogen-protecting unit to the 3-position of the ring system. The addition of sulfur or carbon nucleophiles affords products of preferential capture of the rearrangement intermediate offering a convenient and rapid synthetic route to N-unprotected 2,3-dihydro-3-substituted-1H-benzisoindol-1-ones.The naphthyl amide organic fragment is prevalent in a number of bioactive compounds 1-6 including those targeting the NK1 receptor, 1 the inhibition of aldosterone synthase, 3 the leukocyte proteases cathepsin G 4 and chymase, 5 and a malarial receptor. 2 Aromatic amides including some naphthyl amides are also central to the inhibition of a group of poly(ADP-ribose) polymerase enzymes (PARPs) 7-9 that bind NAD + and have been implicated in the cellular response to DNA injury. 10 The catalytic domain of the PARP enzymes has been shown to be structurally similar to that of bacterial ribosyltransferases, including Pseudomonas aeruginosa exotoxin A, which we are currently studying. PARP inhibitors often contain aromatic amide or lactam functionalities and operate by preferentially binding to the nicotinamide portion of the binding pocket normally occupied by NAD + . 9,11,12 As such, we have targeted novel amides and imides possessing the naphthalene 11 backbone as part of a study to find inhibitors of exotoxin A.Specifically, we have been probing the functionalization of the 2-position of N-protected 1-naphthamides. We applied the Dai protocol for the ortho-metalation of N,Ndisubstituted amides (3.2 equiv s-BuLi, THF, -78°C, 3 h) 13 to monosubstituted amides 1 (a: R = 1,1-diphenylethyl, b: R = cumyl) as a means to introduce additional functionality. Consistent with the literature, 14 the metalation proceeds at the 2-position rather than the 8-position giving dianions 2. Quenching with DMF affords two naphthalimidines (2,3-dihydro-3-hydroxy-1H-benz[e]isoindol-1-ones, 3), which differ only by their protection on the nitrogen (Scheme 1). At this point, nitrogen deprotection was attempted with BF 3 ·OEt 2 15 and a surprising yet parallel manifold of products was obtained for both compounds 3a and 3b. Scheme 2 and the first two entries of Table 1 indicate the assigned structures of the unexpected products. In each product, the nitrogen-protecting group is apparently lost and its carbon skeleton is reattached at the adjacent carbon atom. 16 Scheme 1Three more substrates were prepared in order to establish the generality of the rearrangement. Application of the Dai metalation conditions to the appropriate N-1,1-diphenylethyl and N-cumyl amides gave phthalimidines (2,3-dihydro-3-hydroxy-1H-isoindol-1-ones) 4a (79%) and 4b 15 (67%), respectively, and 3-hydroxy-2,3-dihydro-1H-benz[f]isoindol-1-one (5b, 50%, T...

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Structural Analysis and Optimization of NK₁ Receptor Antagonists through Modulation of Atropisomer Interconversion Properties

Cited by 28 publications

References 41 publications

Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

Review and Modeling of Crystal Growth of Atropisomers from Solutions

A BF₃-Mediated Nitrogen-to-Carbon Rearrangement of N-Protected 2,3-Dihydro-3-hydroxy-1H-benzisoindol-1-ones, and Its Interception for a Facile Preparation of 3-Substituted Benzisoindolones

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Structural Analysis and Optimization of NK1 Receptor Antagonists through Modulation of Atropisomer Interconversion Properties

Cited by 28 publications

References 41 publications

Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

Design and optimization of cyclized NK1 antagonists with controlled atropisomeric properties

Review and Modeling of Crystal Growth of Atropisomers from Solutions

A BF3-Mediated Nitrogen-to-Carbon Rearrangement of N-Protected 2,3-Dihydro-3-hydroxy-1H-benzisoindol-1-ones, and Its Interception for a Facile Preparation of 3-Substituted Benzisoindolones

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Structural Analysis and Optimization of NK₁ Receptor Antagonists through Modulation of Atropisomer Interconversion Properties

A BF₃-Mediated Nitrogen-to-Carbon Rearrangement of N-Protected 2,3-Dihydro-3-hydroxy-1H-benzisoindol-1-ones, and Its Interception for a Facile Preparation of 3-Substituted Benzisoindolones