evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/current...

Evaluation of oxetan-3-ol, thietan-3-ol, and derivatives thereof as bioisosteres of the carboxylic acid functional group Lassalas, P.; Oukoloff, K.; Makani, V.; James, M.; Tran, V.; Yao, Y.; Huang, L.; Vijayendran, K.; Monti, L.; Trojanowski, J. Q.; Lee, V. M.-Y.; Kozlowski, M. C.; Smith, III, A. B.; Brunden, K. R.; Ballatore, C. ACS Med. Chem. Lett. ASAP Celeste Alverez Current Literature 8/5/2017

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Isosteres in Medicinal Chemistry

u  Recent definition:

“Similarities must exist between at least some of the properties of the isostere and those of the fragment being replaced, such that the new analogs retain the biological activities of the parent compound.”

“At the same time, however, the isosteric replacement must produce changes in the physicochemical properties or susceptibility to metabolism compared to the parent compound in order to lead to improved derivatives.”

u  Lassalas et al. J. Med. Chem. 2016, 59, 3183－3203.

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Carboxylic acid Isosteres u  Many reported in literature 8/5/2017

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Lassalas et al. J. Med. Chem. 2016, 59, 3183－3203.

Carboxylic acid Isosteres 8/5/2017 C

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Oxetanes as Isosteres 8/5/2017 C

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Lassalas et al. ACS Med. Chem. Lett. ASAP

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Oxetanes in Medicinal Chemistry 8/5/2017

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u  Modulate lipophilicity

u  Improve solubility, stability

R logD Solubility (μM) Clint (h/m) pKa

CH2 1.8 250 37/520 9.9

gem Me2 2.5 <4 16/420 9.9

oxetane 0.8 18,000 0/43 9.9

Carreira et al. J. Med. Chem., 2010, 53, 3227.

Wipf et al. ACS Med. Chem. Lett. 2014, 5, 900.

aq. solubility = 580 μM aq. solubility = 44,000 μM

Recent Uses of Oxetanes as non-classical Isosteres 8/5/2017

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u  Recently Carreria and Shipman groups have utilized oxetanes to mimic amides and esters

Möller et al. Org. Lett. 2017, 19, 2510－2513.

Synthesis

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Properties of 4-membered Heterocycle Isosteres 8/5/2017

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Why modify Ibuprofen? 8/5/2017 C

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Martel-Pelletier et al. Ann. Rheum. Dis. 2003, 62, 501-509.

Synthesis

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4-Membered Heterocycles in Ibuprofen Analogs

Cmpd PGE2/D2 Assay IC50 (μM)

LBT4 Assay IC50 (μM)

2 0.6 >100

17 31.8 >100

18 28.1 >100

7 34.1 8.4

8 >100 7.6

9 17.4 11.7

10 14.6 20.2

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4-Membered Heterocycles in Ibuprofen Analogs 8/5/2017

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Concentration-response of inhibition of 5-LOX derived LTB4 and COX-derived PGE2/PGD2 by 2 (left) and 10 (right)


Proposed binding modes 8/5/2017 C

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COX-1 crystal structure (PDB: 1EQG)

Proposed binding modes 8/5/2017 C

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COX-1 crystal structure (PDB: 1EQG)

Isosteres of Carboxylic Acids 8/5/2017

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Conclusions

u  The 4-membered heterocyclic replacements of the carbonyl of carboxylic acids lead to improved lipophilicity and permeability

u  Decreased acidity

u  All replacements show weaker H-bonding interactions

u  Oxetan-3-ol and thietan-3-ol and related oxidized products can successfully act as bioisosteres of carboxylic acids

u  Potentially especially useful for CNS applications

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evaluation of oxetan-3-ol, thietan-3-ol, and derivatives ...ccc.chem.pitt.edu/wipf/current...

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