Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury

Journal of Medicinal Chemistry

Volumn 52, Issue 19, 2009, Pages 6012-6023

  MacNevin, Christopher J ^a   Atif, Fahim ^b   Sayeed, Iqbal ^b   Stein, Donald G ^b   Liotta, Dennis C ^a  

^a EMORY UNIVERSITY   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3 ALPHA HYDROXY 5 BETA PREGNAN 20 ONE; 3 BETA HYDROXY 5 ALPHA PREGNAN 20 ONE; 3 BETA HYDROXY PREGN 4 EN 20 ONE; 3 HYDROXY 5 BETA PREGNAN 20 ONE; 3ALPHA HYDROXY 5ALPHA PREGNAN 20 ONE; 5 BETA PREGNAN 3,20 DIONE; HYDROXYPREGN 4 EN 3 ONE; PREGN 4 ENE 3,20 DIOL; PROGESTERONE; PROGESTERONE DERIVATIVE; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BRAIN EDEMA; CONTROLLED STUDY; DRUG EFFICACY; DRUG SCREENING; DRUG SOLUBILITY; DRUG SYNTHESIS; FEMALE; HYDROPHILICITY; MALE; NONHUMAN; RAT; TRAUMATIC BRAIN INJURY;

ANIMALS; BRAIN EDEMA; BRAIN INJURIES; DRUG EVALUATION, PRECLINICAL; FEMALE; KETONES; MALE; MODELS, ANIMAL; OXIMES; PREGNANOLONE; PROGESTERONE; RATS; SOLUBILITY; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 70349637956     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900712n     Document Type: Article

References (66)

1. Langlois, J. A.; Rutland-Brown, W.; Thomas, K. E. Traumatic Brain Injury in the United States: Emergency Department Visits, Hospitalizations, and Deaths; Centers for Disease Control and Prevention, National Center for Injury Prevention and Control: Atlanta, 2006.
2. Thurman, D. J.; Alverson, C.; Dunn, K. A.; Guerrero, J.; Sniezek, J. E. Traumatic brain injury in the United States: a public health perspective. J. Head Trauma Rehab. 1999, 14, 602-615. (Pubitemid 30027268)
3. Finkelstein, E. A.; Corso, P. S.; Miller, T. R. The Incidence and Economic Burden of Injuries in the United States; Oxford University Press: New York, 2006.
4. Tanielian, T.; Jaycox, L. H. Invisible Wounds of War: Psychological and Cognitive Injuries, Their Consequences, and Services to Assist Recovery; RAND Corporation: Santa Monica, CA, 2008.
5. Alderson, P.; Roberts, I. G. Corticosteroids for acute traumatic brain injury. Cochrane Database Syst. Rev. 2005, Issue 1. Art. No. CD000196.
6. Roberts, I.; Schierhout, G.; Alderson, P. Absence of evidence for the effectiveness of five interventions routinely used in the intensive care management of severe head injury: a systematic review. J. Neurol. Neurosurg. Psychiatry 1998, 65, 729-733.
7. Roberts, I.; Yates, D.; Sandercock, P.; Farrell, B.; Wasserberg, J.; Lomas, G.; Cottingham, R.; Svoboda, P.; Brayley, N.; Mazairac, G.; Laloe, V.; Muñoz-Sánchez, A.; Arango, M.; Hartzenberg, B.; Khamis, H.; Yutthakasemsunt, S.; Komolafe, E.; Olldashi, F.; Yadav, Y.; Murillo-Cabezas, F.; Shakur, H.; Edwards, P. Effect of intravenous corticosteroids on death within 14 days in 10008 adults with clinically significant head injury (MRC CRASH trial): randomised placebo-controlled trial. Lancet 2004, 364, 1321-1328.
8. Davies, A. R. Hypothermia improves outcome from traumatic brain injury. Crit. Care Resusc. 2005, 7, 238-243.
9. (a) Clifton, G. L.; Choi, S. C.; Miller, E. R.; Levin, H. S.; Smith, K. R.; Muizelaar, J. P.; Wagner, F. C.; Marion, D. W.; Luerssen, T. G. Intercenter variance in clinical trials of head trauma;experience of the National Acute Brain Injury Study: Hypothermia. J. Neurosurg. 2001, 95, 751-755.
10. (b) Clifton, G. L.; Miller, E. R.; Choi, S. C.; Levin, H. S.; McCauley, S.; Smith, K. R.; Muizelaar, J. P.; Wagner, F. C.; Marion, D. W.; Luerssen, T. G.; Chesnut, R. M.; Schwartz, M. Lack of effect of induction of hypothermia after acute brain injury. N. Engl. J. Med. 2001, 344, 556-563.
11. (c) Alderson, P.; Gadkary, C.; Signorini, D. Therapeutic hypothermia for head injury. Cochrane Database Syst. Rev. 2004, Issue 4. Art. No. CD001048.
12. For preclinical studies, see: (a) Attella, M. J.; Nattinville, A.; Stein, D. G. Hormonal state affects recovery from frontal cortex lesions in adult female rats. Behav. Neural Biol. 1987, 48, 352-367.
13. (b) Roof, R. L.; Duvdevani, R.; Stein, D. G. Gender influences outcome of brain injury: progesterone plays a protective role. Brain Res. 1993, 607, 333-336.
14. (c) Roof, R. L.; Stein, D. G. Progesterone treatment attenuates brain edema following contusion injury in male and female rats. Restor. Neurol. Neurosci. 1992, 4, 425-427.
15. (d) Roof, R. L.; Duvdevani, R.; Braswell, L. Progesterone facilitates cognitive recovery and reduces secondary neuronal loss caused by cortical contusion injury in male rats. Exp. Neurol. 1994, 129, 64-69.
16. (e) Roof, R. L.; Duvdevani, R.; Heyburn, J. W.; Stein, D. G. Progesterone rapidly decreases brain edema: treatment delayed up to 24 h is still effective. Exp. Neurol. 1996, 138, 246-251.
17. (f) Wright, D. W.; Bauer, M. E.; Hoffman, S. W.; Stein, D. G. Serum progesterone levels correlate with decreased cerebral edema after traumatic brain injury in male rats. J. Neurotrauma 2001, 18, 901-909.
18. (g) Goss, C. W.; Hoffman, S. W.; Stein, D. G. Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response study. Pharmacol., Biochem. Behav. 2003, 76, 231-242.
19. (h) Cutler, S. M.; Pettus, E. H.; Hoffman, S. W.; Stein, D. G. Tapered progesterone withdrawal enhances behavioral and molecular recovery after traumatic brain injury. Exp. Neurol. 2005, 195, 423-429.
20. Schumacher, M.; Guennoun, R.; Stein, D. G.; De Nicola, A. F. Progesterone: therapeutic opportunities for neuroprotection and myelin repair. Pharmacol. Ther. 2007, 116, 77-106.
21. (a) Marmarou, A. The pathophysiology of brain edema and elevated intracranial pressure. Cleveland Clin. J. Med. 2004, 71 (Suppl. 1), S6-S8.
22. (b) Marmarou, A.; Signoretti, S. Aygok, G.; Fatouros, P.; Portella, G. Traumatic brain edema in diffuse and focal injury: cellular or vasogenic? Acta Neurochir. 2006, Suppl. 96, 24-29.
23. (c) Duvdevani, R.; Roof, R. L.; Fulop, Z.; Hoffman, S. W.; Stein, D. G. Blood-brain barrier breakdown and edema formation following frontal cortical contusion: does hormonal status play a role? J. Neurotrauma 1995, 12, 65-75.
24. (d) Meffre, D.; Delespierre, B.; Gouezou, M.; Leclerc, P.; Vinson, G. P.; Schumacher, M.; Stein, D. G.; Guennoun, R. The membrane-associated progesterone-binding protein 25-Dx is expressed in brain regions involved in water homeostasis and is up-regulated after traumatic brain injury. J. Neurochem. 2005, 93, 1314-1326. (Pubitemid 40776584)
25. (e) Guo, Q.; Sayeed, I.; Baronne, L. M.; Hoffman, S. W.; Guennoun, R.; Stein, D. G. Progesterone administration modulates AQP4 expression and edema after traumatic brain injury in male rats. Exp. Neurol. 2006, 198, 469-478.
26. (f) Verkman, A. S.; Yang, B.; Song, Y.; Manley, G. T.; Ma, T. Role of water channels in fluid transport studied by phenotype analysis of aquaporin knockout mice. Exp. Physiol. 2000, 85, 233S-241S.
27. (a) Shimamura, K.; Sugino, N.; Yoshida, Y.; Nakamura, Y.; Ogino, K.; Kato, H. Changes in lipid peroxide and antioxidant enzyme activities in corpora lutea during pseudopregnancy in rats. J. Reprod. Fertil. 1995, 105, 253-257.
28. (b) Roof, R. L.; Hoffman, S. W.; Stein, D. G. Progesterone protects against lipid peroxidation following traumatic brain injury in rats. Mol. Chem. Neuropathol. 1997, 31 1-11.
29. (c) Subramanian, M.; Pusphendran, C. K.; Tarachand, U.; Devasagayam, T. P. Gestation confers temporary resistance to peroxidation in the maternal rat brain. Neurosci. Lett. 1993, 155, 151-154.
30. (d) Chao, T. C.; Van Alten, P. J.; Walker, R. J. Steroid sex hormones and macrophage function: modulation of reactive oxygen intermediates and nitrite release. Am. J. Reprod. Immunol. 1994, 32, 43-52.
31. (a) Holmin, S.; Mathiesen, T.; Shetye, J.; Biberfeld, P. Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir. 1995, 132, 110-119.
32. (b) Pettus, E. H.; Wright, D. W.; Stein, D. G.; Hoffman, S. W. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury. Brain Res. 2005, 1049, 112-119.
33. (c) He, J.; Evans, C.-O.; Hoffman, S. W.; Oyesiku, N. M.; Stein, D. G. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury. Exp. Neurol. 2004, 189, 404-412.
34. (d) Holmin, S.; Mathiesen, T. Intracerebral administration of interleukin-1β and induction of inflammation, apoptosis, and vasogenic edema. J. Neurosurg. 2000, 92, 108-120. (Pubitemid 30022094)
35. (e) Knoblach, S. M.; Fan, L.; Faden, A. I. Early neuronal expression of tumor necrosis factor-R after experimental brain injury contributes to neurological impairment. J. Neuroimmunol. 1999, 95, 115-125.
36. (f) Megyeri, P.; Abraham, C. S.; Temesvari, P.; Kovacs, J.; Vas, T.; Speer, C. P. Recombinant human tumor necrosis factor R constricts pial arterioles and increases blood-brain barrier permeability in newborn piglets. Neurosci. Lett. 1992, 148, 137-140.
37. (g) VanLandingham, J. W.; Cekic, M.; Cutler, S.; Hoffman, S. W.; Stein, D. G. Neurosteroids reduce inflammation after TBI through CD55 induction. Neurosci. Lett. 2007, 425, 94-98.
38. (a) Djebaili, M.; Guo, Q.; Pettus, E. H.; Hoffman, S. W.; Stein, D. G. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J. Neurotrauma 2005, 22, 106-118.
39. (b) Djebaili, M.; Hoffman, S. W.; Stein, D. G. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat prefrontal cortex. Neuroscience 2004, 123, 349-359.
40. (a) Mani, S. K. Signaling mechanisms in progesteroneneurotransmitter interactions. Neuroscience 2006, 138, 773-781.
41. (b) Pierson, R. C.; Lyons, A. M.; Greenfield, L. J. Gonadal steroids regulate GABAA receptor subunit mRNA expression in NT2-N neurons. Brain. Res. Mol. Brain. Res. 2005, 138, 105-115.
42. (c) Shen, H.; Gong, Q. H.; Yuan, M.; Smith, S. S. Short-term steroid treatment increases δ GABAA receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioral effects. Neuropharmacology 2005, 49, 573-586.
43. (d) Brann, D. W.; Zamorano, P. L.; De Sevilla, L.; Mahesh, V. B. Expression of glutamate receptor subunits in the hypothalamus of the female rat during the afternoon of the proestrous luteinizing hormone surge and effects of antiprogestin treatment and aging. Neuroendocrinology 2005, 81, 120-128.
44. (a) Chan, J. R.; Phillips, L. J.; Glaser, M. Glucocorticoids and progestins signal the initiation and enhance the rate of myelin formation. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 10459-10464.
45. (b) Ghoumari, A. M.; Ibanez, C.; el-Etr, M.; Leclerc, P.; Eychenne, B.; O'Malley, B. W. Progesterone and its metabolites increase myelin basic protein expression in organotypic slice cultures of rat cerebellum. J. Neurochem. 2003, 86, 848-859.
46. (c) Jung-Testas, I.; Hu, Z. Y.; Baulieu, E. E.; Robel, P. Neurosteroids: biosynthesis of pregnenolone and progesterone in primary cultures of rat glial cells. Endocrinology 1989, 125, 2083-2091. (Pubitemid 19258646)
47. (d) Marin-Husstege, M.; Muggironi, M.; Raban, D.; Skoff, R. P.; Casaccia-Bonnefil, P. Oligodendrocyte progenitor proliferation and maturation is differentially regulated by male and female sex steroid hormones. Dev. Neurosci. 2004, 26, 245-254.
48. (e) Ibanez, C.; Shields, S. A.; el-Etr, M.; Baulieu, E. E.; Schumacher, M.; Franklin, R. J. Systemic progesterone administration results in a partial reversal of the age-associated decline in CNS remyelination following toxin-induced demyelination in male rats. Neuropathol. Appl. Neurobiol. 2004, 30, 80-89.
49. (f) Sim, F. J.; Zhao, C.; Penderis, J.; Franklin, R. J. M. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J. Neurosci. 2002, 22, 2451-2459.
50. Wright, D. A.; Kellermann, A. L.; Hertzberg, V. S.; Clark, P. L.; Frankel, M.; Goldstein, F. C.; Salomone, J. P.; Dent, L. L.; Harris, O. A.; Ander, D. S.; Lowery, D. W.; Patel, M. M.; Denson, D. D.; Gordon, A. B.; Wald, M. M.; Gupta, S.; Hoffman, S. W.; Stein, D. G. ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury. Ann. Emerg. Med. 2007, 49, 391-402.
51. Xiao, G.; Wei, J.; Yan, W.; Wang, W.; Lu, Z. Improved outcomes from the administration of progesterone for patients with acute severe traumatic brain injury: a randomized controlled trial. Crit. Care 2008, 12, R61. (Pubitemid 351650165)
52. (a) VanLandingham, J. W.; Cutler, S. M.; Virmani, S.; Hoffman, S. W.; Covey, D. F.; Krishnan, K.; Hammes, S. R.; Jamnongjit, M.; Stein, D. G. The enantiomer of progesterone acts as a molecular neuroprotectant after traumatic brain injury. Neuropharmacology 2006, 51, 1078-1085. (Pubitemid 44696281)
53. (b) Djebaili, M.; Hoffman, S. W.; Stein, D. G. Allopregnanolone and progesterone decrease cell death and cognitive deficits after a contusion of the rat prefrontal cortex. Neuroscience 2004, 123, 349-359.
54. (c) Djebaili, M.; Guo, Q.; Pettus, E. H.; Hoffman, S. W.; Stein, D. G. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J. Neurotrauma 2005, 22, 106-118.
55. (a) Luche, J.-L. Lanthanides in organic chemistry. 1. Selective 1,2 reductions of conjugated ketones. J. Am. Chem. Soc. 1978, 100, 2226-2227.
56. (b) Luche, J.-L.; Rodriguez-Hahn, L.; Crabbé, P. Reduction of natural enones in the presence of cerium trichloride. J. Chem. Soc., Chem. Commun. 1978, 601-602.
57. Comin, M. J.; Elhalem, E.; Rodriguez, J. B. Cerium ammonium nitrate: a new catalyst for regioselective protection of glycols. Tetrahedron 2004, 60, 11851-11860.
58. (a) Varasi, M.; Walker, K. A. M.; Maddox, M. L. A revised mechanism for the Mitsunobu reaction. J. Org. Chem. 1987, 52, 4235-4238.
59. (b) Purdy, R. H.; Morrow, A. L.; Blinn, J. R.; Paul, S. M. Synthesis, metabolism, and pharmacological activity of 3 R-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J. Med. Chem. 1990, 33, 1572-1581.
60. (a) Bach, G.; Capitaine, J.; Engel, C. R. Steroids and related products. XXV. Cardiotonic steroids. 2. Synthesis of 17 β-substituted 14(15)-unsaturated steroids of the A/B cis series. A. Can. J. Chem. 1968, 46, 733-749.
61. (b) Adéoti, S. B.; Charpentier, B.; Montagnac, A.; Chiaroni, A.; Riche, C.; Pas, M. Introduction of a 14 β-amino function into a steroid nucleus. Application to the cardioactive 14 β-amino-5β-pregnane- 3β,20β-diol starting from progesterone and deoxycholic acid. Tetrahedron 1989, 45, 3717-3730.
62. (a) Soloway, A. H.; Deutsch, A. S.; Gallagher, T. F. Differential reduction of steroid ketones. J. Am. Chem. Soc. 1953, 75, 2356-2358.
63. (b) Mancera, O.; Ringold, H. J.; Djerassi, C.; Rosenkranz, G.; Sondheimer, F. Steroids. XLIII. A ten-step conversion of progesterone to cortisone. The differential reduction of pregnane-3,20-diones with sodium borohydride. J. Am. Chem. Soc. 1953, 75, 1286-1290.
64. Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Delivery Rev. 1997, 23, 3-25.
65. Wieland, P.; Miescher, K. The preparation of polynuclear ketones. Helv. Chim. Acta 1950, 33, 2215-2228.
66. Khouri, N.; Usubillaga, A.; Vaz, S. C.; Delgado, J. N. Synthesis, stereochemical analysis, and neuromuscular blocking activity of oximino ether derivatives of progesterone. J. Pharm. Sci. 1991, 80, 661-664.