INVESTIGATION OF A BICYCLO [1.1.1]PENTANE AS A PHENYL REPLACEMENT WITHIN AN LpPLA 2 INHIBITOR
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1 INVESTIGATION OF A BICYCLO [1.1.1]PENTANE AS A PHENYL REPLACEMENT WITHIN AN LpPLA 2 INHIBITOR Measom, N. D.; Down, K. D.; Hirst, D. J.; Jamieson, C.; Manas, E. S.; Patel, V. K.; and Somers, D. O. Celeste Alverez Current Literature April 15, /15/2017 Celeste Wipf Group 1
2 Propellanes Small-ring propellanes (m,n,l <3): Strained systems that allow for enhanced reactivity Large-ring propellanes (m,n,l 3): Ring strain minimized, appealing for beauty of the structures and the elegance of the synthetic approach Common in natural products Typically 2 of the rings are 5-membered or larger 4/15/2017 Celeste Wipf Group 2 Yang and Cook, J. Org. Chem., 1976, 41, Dilmaç et. al. Angew. Chem. Int. Ed. 2017, 56, 2-37.
3 [1.1.1]Propellane Tricyclo[ ,3 ]pentane Smallest possible propellane Proposed theoretically first in 1972 by Newton and Schulman First synthesized in 1982 by Wiberg and Walker: Largest strain energy (SE) 1.58 Å 1.52 Å Surprisingly stable: bond dissociation energy to the diradical predicted to be 65 kcal/mol Relatively thermally stable: ring opening to methylenecyclobutene at C Wiberg and Walker J. Am. Chem. Soc. 1982, 104, /15/2017 Celeste Wipf Group Wu et. al. Angew. Chem. Int. Ed. 2009, 48, Dilmaç et. al. Angew. Chem. Int. Ed. 2017, 56,
4 [1.1.1]Propellane 4/15/2017 Celeste Wipf Group Dilmaç et. al. Angew. Chem. Int. Ed. 2017, 56,
5 [1.1.1]Propellane Tricyclo[ ,3 ]pentane Smallest possible propellane Proposed theoretically first in 1972 by Newton and Schulman First synthesized in 1982 by Wiberg and Walker: Largest strain energy (SE) 1.58 Å 1.52 Å Surprisingly stable: bond dissociation energy to the diradical predicted to be 65 kcal/mol Relatively thermally stable: ring opening to methylenecyclobutene at C Wiberg and Walker J. Am. Chem. Soc. 1982, 104, /15/2017 Celeste Wipf Group Wu et. al. Angew. Chem. Int. Ed. 2009, 48, Dilmaç et. al. Angew. Chem. Int. Ed. 2017, 56,
6 Propellanes as Isosteres Bioisostere: replacement of an atom or structural feature that results in similar biological effects as the parent Replacement can maintain physiochemical properties or topology Distances between key carbon atoms Dihedral angles Phenyl Cubane [1.1.1] Bicyclopentane Cambridge MedChem Consulting: Bioisostere 4/15/2017 Celeste Wipf Group Stepan et al. J. Med. Chem. 2012, 55, Costantion et. al. Bioorg. Med. Chem. 2001, 9,
7 Propellanes in Drugs Good isosteric replacement: Poor isosteric replacement: Stepan et. al. J. Med. Chem. 2012, 55, Pellicciari et. al. J. Med. Chem., 1996, 39, /15/2017 Celeste Wipf Group Nicolaou et. al. ChemMedChem, 2016, 11,
8 Propellanes in Drugs Poor isosteric replacement: 4/15/2017 Celeste Wipf Group Nicolaou et. al. ChemMedChem, 2016, 11,
9 Stability of Propellane Analogs Aroclor-induced rat liver S9 (30 min) Human liver s9 (30 min) Rat hepatocytes (2 h) Human hepatocytes (2 h) Rat bile ducts (0-24 h) Rat plasma (0.5, 1, 3, 6, 24 h) ND = Not Determined P = Phosphocholine methine Metabolism on the bicycle[1.1.1]pentane moiety Parent Mono-Ox P Da Bis-Ox Mono-/Bis-Ox + dehydrogenation 4/15/2017 Celeste Wipf Group Zhou et. al. Drug Metab. Dispos. 2016, 44, Metabolism on other moieties Mono-Ox, ect ND ND ND ND 99 <1 ND ND ND ND 99 <1 ND ND ND ND 99 <1 ND ND ND ND 4 55 (2-1), 6 6 (2-3) 4 (1 pdt) 18 (4 pdts) ND ND ND ND ND
10 Stability of Propellane Analogs 4/15/2017 Celeste Wipf Group Zhou et. al. Drug Metab. Dispos. 2016, 44,
11 Stepan et. al. J. Med. Chem. 2012, 55, PK Properties of Propellanes 1 3 IC 50 (Aβ 42, nm) a, b (52) (4) Notch selectivity b 350 (14) 178 (4) human hepatocytes CL int,app (µl/min/million cells) c 15.0 <3.80 HLM CL int,app (ml/min/kg) b, d <16.2 (4) <8.17 (2) RRCK P app (A to B)(10 6 cm/s) e ElogD f kinetic solubility (ph = 6.5, µm) thermodynamic solubility (ph = 6.5, µm) thermodynamic solubility (ph = 7.4, µm) MDR1/MDCKBA/AB ratio g
12 LpPLA 2 Lipoprotein-associated phospholipase A 2 or Platelet-activating factor acetylhyrolase (PAF-AH) Plays a role in atherosclerosis and diseases associated with vascular inflammation (ie. Alzheimer s disease) Elevated levels linked to increased risk for: Myocardial infarction Ischemic stroke Cardiac death in patients with cardiovascular disease 2 GSK compounds: 4/15/2017 Celeste Wipf Group 12 ACS Med. Chem. Lett. 2017, 8, 43 48
13 Binding vs. Phenyl (Docking) X-ray crystal structure of darapladib (blue) in LpPLA2 overlaid with modeled bioisosteric replacement (magenta) 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
14 Propellane Synthesis Reagents and conditions: (i) 4-bromotrifluorotoluene, nbuli, THF, 78 C to rt, 77%; (ii) conc. HCl, PhMe, rt, sonication, 75%; (iii) HCl, MeOH, 1,4-dioxane, rt, quant.; (iv) NaH, THF, rt, 98%; (v) sodium trichloroacetate, tetrachloroethylene, diglyme, C, 38%; (vi) TTMSS, 1,1 -azobis (cyclohexanecarbonitrile), PhMe, 110 C, 74%; (vii) LiOH, 1,4-dioxane, rt, 95%. 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
15 Darapladib Analog Synthesis Reagents and conditions: (i) 14, T3P, Et 3 N, EtOAc, rt, 99%; (ii) LiAlH 4, THF, rt, 56%; (iii) 17, T3P, Et 3 N, rt, CH 2 Cl 2, 60% 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
16 Rilapladib Analog Synthesis Reagents and conditions: (i) 18, T3P, Et 3 N, CH 2 Cl 2, rt, 74%; (ii) [Ir(COE) 2 Cl] 2, Et 2 SiH 2, CH 2 Cl 2, rt, 59%; (iii) 21, T3P, Et 3 N, CH 2 Cl 2, rt, 53%. 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
17 Binding vs. Phenyl (X-Ray) X-ray crystal structure overlays of bound darapladib (blue) and analogue 5 (magenta) in LpPLA2 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
18 Physiochemical/PK Properties Darapladib 5 Rilapladib 22 pic NT Kinetic Solubility (um) 8 74 <1 32 Thermodynamic Solubility (simulated intestinal sol.) [ug/ml] 399 > Permeability (nm/s) NT NT Lipophilicity (ChromLogD 7.4 ) PFI (Property Forcast Index) CL (HLM) [ml/min/g] NT = Not tested 4/15/2017 Celeste Wipf Group ACS Med. Chem. Lett. 2017, 8,
19 Summary The bioisosteric replacement of a phenyl ring with bicyclo [1.1.1]pentane within Darapladib and Rilpladib was successful carried out and resulted in improved physiochemical properties In Darapladib the bicyclo[1.1.1]pentane maintained high potency The bicyclo[1.1.1]pentane did not disrupt the binding mode of the parent compound, but did shorten the side chain with respect to the biaryl Bicyclo[1.1.1]pentane is useful in LpPLA 2 inhibition 4/15/2017 Celeste Wipf Group 19
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