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. 2020 Jun 3;11(7):1386–1391. doi: 10.1021/acsmedchemlett.0c00061

Design and Development of a Macrocyclic Series Targeting Phosphoinositide 3-Kinase δ

Jonathan A Spencer †,‡, Ian R Baldwin †, Nick Barton †, Chun-Wa Chung †, Máire A Convery †, Christopher D Edwards †, Craig Jamieson ‡, David N Mallett †, James E Rowedder †, Paul Rowland †, Daniel A Thomas †, Charlotte J Hardy †,*
PMCID: PMC7357223  PMID: 32676144

Abstract

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A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

Keywords: Macrocycle, PI3Kδ, Thermodynamics, Lipid kinase

Phosphoinositide 3-kinase δ (PI3Kδ) is a lipid kinase that catalyzes the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is a signaling molecule with roles in key processes such as cell growth, proliferation, survival, and migration.1−3 PI3Kδ is predominantly expressed in leukocytes1 and is an established target for diseases such as chronic obstructive pulmonary disease,4−6 oncology conditions such as chronic lymphocytic leukemia,7 and Sjögren’s syndrome.8

Ongoing work within our laboratories has identified the benzoxazine series of inhibitors (e.g., compound 1) as a promising opportunity to provide clinical candidates. An analysis of the binding mode of compound 1 by X-ray crystallography highlighted the proximity of the six-substituent of the benzoxazine core and the sulfonamide substituent from the pyridine, with room to accommodate a linker between them (Figure 1) and generate a macrocycle.

Figure 1.

Figure 1

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Protein-bound X-ray crystal structure of compound 1 (PDB: 6ZAA, 2.5 Å), with the hinge binder located at the rear of the image, highlighting the potential for macrocyclization within the template.

Macrocyclization is an established strategy for modulating properties9−11 such as potency by constraining the conformation close to the bioactive pose,12,13 selectivity by reducing the available binding modes,14 permeability by reducing the molecular volume,12 and clearance by restricting binding to metabolizing enzymes or by providing a steric block,12 as well as offering structural novelty.15 It was therefore of interest to explore the effect of macrocyclization within the emerging benzoxazine template for targeting PI3Kδ.

Initial efforts focused on the design and synthesis of analogues of the progenitor compound 2, a simplified analogue of key compound 1 (Figure 2). On the basis of the previous structure–activity relationship (SAR) from the template and computational modeling, both amine and amide linkers at the benzoxazine six-position were selected. A variety of linker lengths as well as both forward and reverse sulfonamides on the pyridine were explored.

Figure 2.

Figure 2

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Progenitor compound and exemplar macrocyclic targets.

The analysis of the potency data showed that macrocyclic linkers were generally tolerated at the PI3Kδ binding site (Table 1). Within the aryl S-linked sulfonamide series (2–15), reductions in potency were observed with ethylene-linked compounds 6 and 13. We reasoned that this was a result of the short linker length, preventing optimal interactions at the core of the molecule. Hence longer linkers were explored in more depth. With propylene and butylene linkers, only modest increases or small decreases in potency and ligand efficiency were observed. The compound with the largest potency increase was butylene-linked macrocycle 8, which exhibited a 10-fold potency increase over its progenitor compound 2. However, this linker is likely to have significant flexibility; therefore, further optimization should be possible.

Table 1. pIC50 Data Measured in a PI3Kδ Enzyme Assay (All Data N ≥ 2; SD ≤ 0.45)b.

graphic file with name ml0c00061_0006.jpg

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a

Compound measured as <4.5 once.

b

ND = compound not selected for synthesis.

Alternative aryl N-linked sulfonamide compounds were also explored. It was proposed that differences in the sulfonamide orientation could provide a more favorable vector for cyclization, and hence the requisite progenitor and macrocyclic compounds were designed and synthesized.

Within the aryl N-linked sulfonamide series (16–25), more dramatic increases in potency were observed, with all macrocyclic compounds having higher potency and efficiency than the corresponding progenitor compounds. The largest increases were observed for the ethylene-linked compounds 19 and 24. This contrasts with the S-linked sulfonamide series, where these were the least potent compounds, suggesting that for the N-linked series, the conformational constraint is favorable for binding. Propylene- and butylene-linked compounds were found to have more modest increases in potency.

Macrocycle 19 and progenitor 18 were selected for further study due to the greater than 30-fold increase in potency and corresponding efficiency increase observed for these compounds. Macrocycle 19 was synthesized according to Scheme 1. The synthesis of other macrocycles and progenitor compounds is available in the Supporting Information using analogous synthetic procedures.

Scheme 1. Synthesis of Key Macrocycle Compound 19.

Scheme 1

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Reagents and conditions: (a) CbzCl, aq. NaOH, 58%; (b) SOCl2, toluene, 94%; (c) pyridine, 21%; (d) 27, Pd2(dba)3, RuPhos, Cs2CO3,25%; (e) LiOH, THF, H2O, 69%; (f) H2, Pd/C, THF, EtOAc, 64%; (g) MsCl, imidazole, DCM, 21%; (h) BH3·DMS, THF, MeOH, 10%; (i) 1,2-dibromoethane, K2CO3, DMF, 85%.

Macrocycle 19 could be accessed from commercially available starting material 28. Carboxybenzyl protection16 and sulfonyl chloride formation17 yielded intermediate 29. Sulfonamide formation with commercial amine 30 gave sulfonamide 31. Buchwald–Hartwig amination18 with benzoxazine 27, synthesized by the double alkylation of amino alcohol 26, afforded the cross-coupled product 32. This was then deprotected by ester hydrolysis and hydrogenolysis to reveal amino acid 33. Intramolecular cyclization with mesyl chloride furnished macrocycle 24. The macrocyclization step generally proved challenging, with only low to moderate yields obtained in most examples. The subsequent lactam reduction with borane gave macrocycle product 19.

A number of strategies were explored to further rationalize the origin of the potency increase noted upon the cyclization of progenitor 18 to macrocycle 19. First, protein-bound X-ray crystal structures were generated for these compounds to explore the binding modes (Figure 3).

Figure 3.

Figure 3

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Overlay of the protein-bound X-ray crystal structures of macrocycle 19 (PDB: 6ZAD, 2.2 Å) and progenitor 18 (PDB: 6ZAC, 2.2 Å). Protein not shown.

The analysis of these structures revealed that the binding modes for the progenitor and macrocycle are almost identical. The formation of the macrocycle does not negatively impact the key binding interactions from the conserved core structure. We therefore proposed that the compound pair would have similar enthalpic contributions to binding, with the reduced conformational freedom of the macrocycle providing a reduced entropic penalty to binding and a resultant increase in potency. This is supported by an unconstrained conformational search for compounds 18 and 19, which indicates an increased preference for sulfonamide conformations close to the bioactive conformation in the case of the macrocycle, 19, compared with progenitor, 18 (figure in the Supporting Information). Interestingly, the analysis of the amine end of the macrocyclic linker indicated that the bioactive conformation was one of the least preferred observed dihedral angles in macrocycle 19, indicating that this linker may still be suboptimal.

To further investigate the thermodynamics of binding, the entropic and enthalpic contributions to binding were experimentally derived using surface plasmon resonance (SPR). The SPR data were used to construct a van’t Hoff analysis for both compounds,19,20 and the entropy and enthalpy of binding were obtained (Table 2).

Table 2. Results of the van’t Hoff Analysis of SPR Data.

  progenitor 18 macrocycle 19
ΔG25°C (kJ mol–1) –37.3 –48.8
ΔH (kJ mol–1) –58.9 –0.7
ΔS (J K–1 mol–1) –72.5 159.9
pKd 25 °C 6.6 8.4
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The data obtained were consistent with the potency increase from progenitor to macrocycle; a more favorable Gibb’s free energy change of binding and a corresponding increase in pKd were observed. Also, as expected, the van’t Hoff analysis showed that the macrocycle had a reduced entropic penalty to binding, hypothesized, in part, to be due to the reduced conformational freedom in the unbound state. The magnitude of the positive entropic contribution and the reduction of the enthalpic contribution to close to zero were surprising; however, it is well precedented that accurately predicting the thermodynamics of ligand binding is challenging due to the complexity of the system (i.e., ligand, protein, and solvent effects).21,22

Next, we wished to explore the effect of macrocyclization on the biological and biophysical properties within the template (Table 3).

Table 3. Comparison of Key Developability Properties between Progenitor 18 and Macrocycle 19.

    progenitor 18 macrocycle 19
pIC50PI3Kδ (LE, LipE), N ≥ 3 6.2 (0.31, 4.6) 7.7 (0.39, 3.4)
pIC50PI3K α, β, γ, N ≥ 3 4.9a, 5.1, 4.6b 5.6, 5.9, 5.8
whole blood pIC50,cN = 3 5.8 6.5
Chrom logDpH 7.4 1.6 4.3
CLND solubility (μM) ≥406 ≥331
AMP (nm s–1) 140 530
HSA/AGP, % binding 37/64 88/70
pKaH 9.4 5.7
in vitro clearance (mL min–1 kg–1) Mic    
(human, <0.40 <0.40
minipig, 1.63 0.92
rat) 0.48 <0.46
Hep    
(human, <0.45 <0.45
minipig, <0.89 <0.89
rat) <0.80 <0.80
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a

Compound measured as <4.5 on one occasion.

b

Compound measured as <4.5 on three occasions; SD ≤ 0.32 (enzyme assays); SD ≤ 0.51 (cellular assay).

c

IFNγ inhibition in CytoStim-stimulated whole blood assay.

As previously stated, macrocycle 19 exhibits increased potency and ligand efficiency compared with progenitor 18. This also translates into a more modest increase in whole blood potency. It was expected that macrocycle 19 would have similar selectivity over the closely related PI3K isoforms; however, a trend toward slightly improved selectivity was observed. This is possibly due to the restricted conformations of the macrocycle.

Macrocycle 19 is more lipophilic than progenitor 18 and therefore has a lower lipophilic efficiency (LipE), probably due to the decreased ability to hydrogen bond within the restricted template. This is reflected in the measured pKaH, with a significantly lower basicity for the cyclic amine compared with the acyclic analogue, a trend observed in multiple macrocycle/progenitor pairs across all linker lengths (full data not shown). Given the magnitude of the difference, it is hypothesized that in addition to the inductive effect of the sulfonamide on the amine pKaH, the macrocycle may also provide a steric block to the amine lone pair, thereby further reducing the basicity. This is supported by the lowest energy conformation orientating the lone pair toward the center of the ring (Figure 4).

Figure 4.

Figure 4

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Lowest energy conformation of macrocycle 19. The protonated form is shown to indicate the directionality of the lone pair.

The high lipophilicity results in highly permeable compounds; however, aqueous solubility is also maintained. Additionally, the increase in lipophilicity is not reflected in higher clearance, with both compounds displaying in vitro clearances close to the lower limit of the hepatocyte assay threshold across species. The lipophilicity does result in an increase in plasma protein binding; however, this still falls within acceptable ranges for both compounds. In summary, although it is more lipophilic with a lower LiPE, macrocycle 19 does not exhibit many of the associated poor developability properties.23

Given that the in vitro clearance data showed low clearance, both of the compounds were advanced into a rat in vivo PK study to further evaluate the differences in clearance (Table 4).

Table 4. Intravenous Rat PK Data for Compounds 18 and 19.

  progenitor 18 macrocycle 19
in vivo Cl (mL min–1 kg–1) 233 12.3
Vdss (L kg–1) 8.5 1.8
half life (h) 0.60 1.5
predicted Fu (based on HSA, AGP, and CMR)24 0.40 0.06
Clunbound (mL min–1 kg–1) 587 192
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The macrocycle displays much lower in vivo clearance in the rat compared with the progenitor compound, suggesting that the macrocycle could be suitable for oral delivery. Pleasingly, on calculating the unbound clearance using a validated biomimetic model for predicting the unbound human fraction (Fu)24 and assuming that the Fu is species-independent, it is clear that this improvement results from a true modulation of the intrinsic clearance and is not just a secondary effect of reducing the free fraction available to be cleared (Table 4). It is hypothesized that this reduced clearance is due to the macrocyclic restriction preventing access to conformations required to bind to some metabolizing enzymes.

In summary, it has been shown that macrocyclization within a series of PI3Kδ inhibitors can provide differentiated compounds, with improvements in potency, permeability, and in vivo clearance shown with key exemplars. The analysis of the thermodynamics of binding for one pair of compounds also highlights the entropic advantage of macrocyclization. These data further support macrocyclization as an attractive strategy for lead optimization.

Acknowledgments

We thank the EPSRC for funding via Prosperity Partnership EP/S035990/1. We thank members of Screening, Profiling and Mechanistic Biology, GSK for screening; members of Protein & Cellular Sciences, GSK for protein production; and members of Discovery Analytical, GSK for physicochemical profiling.

Glossary

Abbreviations

PI3K

phosphoinositide 3-kinase

LE

ligand efficiency

ND

not determined

IFNγ

interferon gamma

SPR

surface plasmon resonance

CLND

chemiluminescent nitrogen detection

AMP

artificial membrane permeability

HSA

human serum albumin

AGP

α-1-glycoprotein

h

human

mp

minipig

r

rat

RuPhos

2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl

PIP2P

phosophatidylinositol 4,5-bisphosphate

PIP3

phosophatidylinositol 3,4,5-trisphosphate

Vdss

steady-state volume of distribution

Clunbound

unbound clearance

CMR

calculated molar refractivity

DCM

dichloromethane

dba

dibenzylideneacetone

PK

pharmacokinetics

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.0c00061.

  • Synthetic procedures and characterization of PI3Kδ inhibitors, PI3Kδ assay data, conformational search results, and SPR data for compounds 18 and 19 and PI3Kδ crystallography methods and data statistics for compounds 1, 18, and 19 (PDF)

Accession Codes

Coordinates have been deposited with the Protein Data Bank (compound 1: 6ZAA, compound 18: 6ZAC; compound 19: 6ZAD).

Author Present Address

§ J.A.S. and C.J.H.: Charles River Laboratories, Saffron Walden, Essex, CB10 1XL, U.K.

Author Present Address

∥ D.A.T.: Arctoris, 120 East Olympic Avenue, Milton Park, Abingdon, OX14 4SA, U.K.

Author Contributions

All authors have given approval to the final version of the manuscript.

The authors declare the following competing financial interest(s): All authors except J.A.S and C.J. were employees of GlaxoSmithKline at the time the work was carried out.

Notes

All animal studies were ethically reviewed and carried out in accordance with the Animals (Scientific Procedures) Act 1986 and the GSK Policy on the Care, Welfare and Treatment of Animals.

Supplementary Material

ml0c00061_si_001.pdf (1.5MB, pdf)

References

  1. Foster J. G.; Blunt M. D.; Carter E.; Ward S. G. Inhibition of PI3K Signaling Spurs New Therapeutic Opportunities in Inflammatory/Autoimmune Diseases and Hematological Malignancies. Pharmacol. Rev. 2012, 64 (4), 1027–1054. 10.1124/pr.110.004051. [DOI] [PubMed] [Google Scholar]
  2. Engelman J. A.; Luo J.; Cantley L. C. The Evolution of Phosphatidylinositol 3-Kinases as Regulators of Growth and Metabolism. Nat. Rev. Genet. 2006, 7, 606. 10.1038/nrg1879. [DOI] [PubMed] [Google Scholar]
  3. Mcnamara C. R.; Degterev A. Small-Molecule Inhibitors of the PI3K Signaling Network. Future Med. Chem. 2011, 3 (5), 549–565. 10.4155/fmc.11.12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Down K.; Amour A.; Baldwin I. R.; Cooper A. W. J.; Deakin A. M.; Felton L. M.; Guntrip S. B.; Hardy C.; Harrison Z. A.; Jones K. L.; Jones P.; Keeling S. E.; Le J.; Livia S.; Lucas F.; Lunniss C. J.; Parr N. J.; Robinson E.; Rowland P.; Smith S.; Thomas D. A.; Vitulli G.; Washio Y.; Hamblin J. N. Optimization of Novel Indazoles as Highly Potent and Selective Inhibitors of Phosphoinositide 3-Kinase δ for the Treatment of Respiratory Disease. J. Med. Chem. 2015, 58 (18), 7381–7399. 10.1021/acs.jmedchem.5b00767. [DOI] [PubMed] [Google Scholar]
  5. Finan P. M.; Thomas M. J. PI 3-Kinase Inhibition: A Therapeutic Target for Respiratory Disease. Biochem. Soc. Trans. 2004, 32 (2), 378–382. 10.1042/bst0320378. [DOI] [PubMed] [Google Scholar]
  6. To Y.; Ito K.; Kizawa Y.; Failla M.; Ito M.; Kusama T.; Elliott W. M.; Hogg J. C.; Adcock I. M.; Barnes P. J. Targeting Phosphoinositide-3-Kinase-δ with Theophylline Reverses Corticosteroid Insensitivity in Chronic Obstructive Pulmonary Disease. Am. J. Respir. Crit. Care Med. 2010, 182 (7), 897–904. 10.1164/rccm.200906-0937OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Furman R. R.; Sharman J. P.; Coutre S. E.; Cheson B. D.; Pagel J. M.; Hillmen P.; Barrientos J. C.; Zelenetz A. D.; Kipps T. J.; Flinn I.; Ghia P.; Eradat H.; Ervin T.; Lamanna N.; Coiffier B.; Pettitt A. R.; Ma S.; Stilgenbauer S.; Cramer P.; Aiello M.; Johnson D. M.; Miller L. L.; Li D.; Jahn T. M.; Dansey R. D.; Hallek M.; O’Brien S. M. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia. N. Engl. J. Med. 2014, 370 (11), 997–1007. 10.1056/NEJMoa1315226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bieth B.; Burkhart C.; Christ A.; De Buck S.; Kalis C.; Lindgren S.. Use of Inhibitors of the Activity or Function of PI3K for the Treatment of Primary Sjoegren’s Syndrome. WO2017118965A1, 2017.
  9. Driggers E.; Hale S.; Lee J.; Terrett N. K. The Exploration of Macrocycles for Drug Discovery — An Underexploited Structural Class. Nat. Rev. Drug Discovery 2008, 7, 608–624. 10.1038/nrd2590. [DOI] [PubMed] [Google Scholar]
  10. Giordanetto F.; Kihlberg J. Macrocyclic Drugs and Clinical Candidates: What Can Medicinal Chemists Learn From Their Properties?. J. Med. Chem. 2014, 57 (2), 278–295. 10.1021/jm400887j. [DOI] [PubMed] [Google Scholar]
  11. Stachel S. J.; Coburn C. A.; Sankaranarayanan S.; Price E. A.; Pietrak B. L.; Huang Q.; Lineberger J.; Espeseth A. S.; Jin L.; Ellis J.; Holloway M. K.; Munshi S.; Allison T.; Hazuda D.; Simon A. J.; Graham S. L.; Vacca J. P. Macrocyclic Inhibitors of -Secretase: Functional Activity in an Animal Model. J. Med. Chem. 2006, 49 (21), 6147–6150. 10.1021/jm060884i. [DOI] [PubMed] [Google Scholar]
  12. Johnson T. W.; Richardson P. F.; Bailey S.; Brooun A.; Burke B. J.; Collins M. R.; Cui J. J.; Deal J. G.; Deng Y. L.; Dinh D.; Engstrom L. D.; He M.; Hoffman J.; Hoffman R. L.; Huang Q.; Kania R. S.; Kath J. C.; Lam H.; Lam J. L.; Le P. T.; Lingardo L.; Liu W.; Mctigue M.; Palmer C. L.; Sach N. W.; Smeal T.; Smith G. L.; Stewart A. E.; Timofeevski S.; Zhu H.; Zhu J.; Zou H. Y.; Edwards M. P. Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(metheno)pyrazolo[4,3-H][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), A Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and C-Ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency Against ALK-Resistant Mutations. J. Med. Chem. 2014, 57 (11), 4720–4744. 10.1021/jm500261q. [DOI] [PubMed] [Google Scholar]
  13. Mccoull W.; Abrams R. D.; Anderson E.; Blades K.; Barton P.; Box M.; Burgess J.; Byth K.; Cao Q.; Chuaqui C.; Carbajo R. J.; Cheung T.; Code E.; Ferguson A. D.; Fillery S.; Fuller N. O.; Gangl E.; Gao N.; Grist M.; Hargreaves D.; Howard M. R.; Hu J.; Kemmitt P. D.; Nelson J. E.; O’Connell N.; Prince D. B.; Raubo P.; Rawlins P. B.; Robb G. R.; Shi J.; Waring M. J.; Whittaker D.; Wylot M.; Zhu X. Discovery of Pyrazolo[1,5-A]Pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors. J. Med. Chem. 2017, 60 (10), 4386–4402. 10.1021/acs.jmedchem.7b00359. [DOI] [PubMed] [Google Scholar]
  14. Mann A.Conformational Restriction and/or Steric Hindrance in Medicinal Chemistry. In The Practice of Medicinal Chemistry; Wermuth C. G., Ed.; Academic Press: London, 2008. [Google Scholar]
  15. William A. D.; Lee A. C.-H.; Blanchard S.; Poulsen A.; Teo E. L.; Nagaraj H.; Tan E.; Chen D.; Williams M.; Sun E. T.; Goh K. C.; Ong W. C.; Goh S. K.; Hart S.; Jayaraman R.; Pasha M. K.; Ethirajulu K.; Wood J. M.; Dymock B. W. Discovery of the Macrocycle 11-(2-Pyrrolidin-1-yl-ethoxy)-14,19-dioxa-5,7,26-triaza-tetracyclo[19.3.1.1(2,6).1(8,12)]heptacosa-1(25),2(26),3,5,8,10,12(27),16,21,23-decaene (SB1518), A Potent Janus Kinase 2/Fms-Like Tyrosine Kinase-3 (JAK2/FLT3) Inhibitor for the Treatment of Myelofibrosis and Lymphoma. J. Med. Chem. 2011, 54 (13), 4638–4658. 10.1021/jm200326p. [DOI] [PubMed] [Google Scholar]
  16. Moree W. J.; Van Gent L. C.; Van Der Marel G. A.; Liskamp R. M. J. Synthesis of Peptides Containing a Sulfinamide or a Sulfonamide Transition-State Isostere. Tetrahedron 1993, 49 (5), 1133–1150. 10.1016/S0040-4020(01)86293-1. [DOI] [Google Scholar]
  17. Sutherland H.; Shriner R. L. Anomalous Mutarotation of Salts of Reychler’s Acid. IV. Comparison of 2-(N-Phenylketimine)-D-Camphane-10-Sulfonic Acid with D-Camphor-10-Sulfonanilide. J. Am. Chem. Soc. 1936, 58 (1), 62–63. 10.1021/ja01292a019. [DOI] [Google Scholar]
  18. Surry D. S.; Buchwald S. L. Dialkylbiaryl Phosphines in Pd-Catalyzed Amination: A User’s Guide. Chem. Sci. 2011, 2 (1), 27–50. 10.1039/C0SC00331J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Day Y. S. N.; Baird C. L.; Rich R. L.; Myszka D. G. Direct Comparison of Binding Equilibrium, Thermodynamic, and Rate Constants Determined by Surface- and Solution-Based Biophysical Methods. Protein Sci. 2002, 11 (5), 1017–1025. 10.1110/ps.4330102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. De Mol N. J.; Dekker F. J.; Broutin I.; Fischer M. J.; Liskamp R. M. Surface Plasmon Resonance Thermodynamic and Kinetic Analysis as a Strategic Tool in Drug Design. Distinct Ways for Phosphopeptides to Plug Into Src- And Grb2 SH2 Domains. J. Med. Chem. 2005, 48 (3), 753–63. 10.1021/jm049359e. [DOI] [PubMed] [Google Scholar]
  21. Delorbe J. E.; Clements J. H.; Whiddon B. B.; Martin S. F. Thermodynamic and Structural Effects of Macrocyclization as a Constraining Method in Protein-Ligand Interactions. ACS Med. Chem. Lett. 2010, 1 (8), 448–452. 10.1021/ml100142y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Benfield A. P.; Teresk M. G.; Plake H. R.; Delorbe J. E.; Millspaugh L. E.; Martin S. F. Ligand Preorganization may be Accompanied by Entropic Penalties in Protein–Ligand Interactions. Angew. Chem., Int. Ed. 2006, 45 (41), 6830–6835. 10.1002/anie.200600844. [DOI] [PubMed] [Google Scholar]
  23. Stepan A. F.; Kauffman G. W.; Keefer C. E.; Verhoest P. R.; Edwards M. Evaluating the Differences in Cycloalkyl Ether Metabolism Using the Design Parameter “Lipophilic Metabolism Efficiency” (Lipmete) and a Matched Molecular Pairs Analysis. J. Med. Chem. 2013, 56 (17), 6985–6990. 10.1021/jm4008642. [DOI] [PubMed] [Google Scholar]
  24. Valko K. L.; Teague S. P.; Pidgeon C. In Vitro Membrane Binding and Protein Binding (IAM MB/PB Technology) to Estimate In Vivo Distribution: Applications in Early Drug Discovery. ADMET DMPK 2017, 5 (1), 14–38. 10.5599/admet.5.1.373. [DOI] [Google Scholar]

Associated Data

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Supplementary Materials

ml0c00061_si_001.pdf (1.5MB, pdf)

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