Benzothiazines As Novel Peptide Mimetic Calpain Inhibitors
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Discovery and development of a novel peptidomimetic for potential treatment of ischemic stroke or traumatic spinal cord injury.
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Benzothiazines As Novel Peptide Mimetic Calpain Inhibitors
- 1. 3,4-Dihydro-1,2-Benzothiazine-1,1-dioxides as Novel Peptide Mimetic Calpain I Inhibitors
- 6. Role of Calpain in Ischemic Neurodegeneration Calpain Activation AMPA NMDA Voltage- gated Ca +2 Ca +2 Hydrolysis of Cytoskeletal Proteins Neuronal Cell Death Kemp, TIPS (1994) Bigge, Ann Rep Med Chem, 29 , 13 (1994) Siman, Neurotox Excit Amino Acids , p.145 (1990) Ca +2 Ca +2 Ca +2 Ca +2 Ca +2
- 8. Inhibitor Classes Reversible Irreversible
- 12. Cephalon Side-chain Optimization Summary of SAR from >100 L,L-Dipeptidyl aldehydes P 2 : Specific Leu > Val ~ Nle > Ile Capping Group: Tolerant Z ~ 4-Nitro-Z > Ts ~ (+)-Menthyloxy-CO ~ FMOC >> Ac P 1 : Tolerant Val > Cha ~ Leu > Nle His ~ Phe ~ Met > Arg Most potent inhibitor IC 50 = 4nM Iqbal, et al., Bioorg. Med. Chem. Lett. 1997, 7, 539
- 13. P 2 -D-Amino Acid Analogs Calpain I IC 50 = 11nM Chatterjee, Bihovsky JMC , 1998, 41, 2663 Molt-4 IC 50 = 1.4 M 10 130 Calpain I IC 50 (nM) Molt-4 IC 50 ( M) X 0.9 ND H
- 15. P 2 -Achiral, P ’ -Extended a-Ketoamides Chatterjee, Bihovsky, Wells BMCL , 1999, 2371 K i (nM) R K i (nM) R 62 PhCH(CH 3 )(CH 2 ) 2 - 26 2,6-Dichlorophenyl 1100 Ph(CH 2 ) 3 - 49 2,5-Dichlorophenyl 21 (CH 3 ) 2 CHCH 2 CH 2 - 46 2-Chloro-5-methoxyphenyl 420 (CH 3 ) 2 CHCH 2 - 130 2,6-Dimethylphenyl 1100 (CH 3 ) 2 CH- 430 3,5-Bis(trifluoromethyl)phenyl 57 2,6-Dichloronicotinyl >1000 3,4-Methylenedioxyphenyl 14 2,6-Difluorophenyl 570 Phenyl
- 16. P 2 -Achiral, P’-Extended a-Ketoamides X K i (nM) 14 21 8 59 71 15
- 21. General Synthesis Popel Pharmazie, 1980, 266
- 22. a Mixture of (3R)- and (3S)- diastereomers; b Isomer 1 is the (3S)- diastereomer . Wells, Bihovsky, Tao, Mallamo JMC , 2001, 44, 3488 3,4-Dihydro-1,2-benzothiazine 1,1-dioxide peptidomimetic aldehydes
- 23. Excellent selectivity compared to dipeptide aldehydes Structure >>1000 (44%@1 M) 7 82 11 5 20 38 11 Cathepsin B IC 50 (nM) Calpain I IC 50 (nM)
- 25. Unsaturated Analogs 3.2 2.1 0.9 2.9 Molt-4 Cell IC 50 ( M) 37 OMe Me H H 8 H CH 2 CH 3 OCH 2 CH 2 O 6 H Me OCH 2 CH 2 O 15 H Me Cl Cl Calpain I IC 50 (nM) R4 R3 R2 R1
- 26. Benzothiadiazine Analogs 28 OCH 2 CH 2 O 83 H H Calpain I IC 50 (nM) R 2 R 1
- 27. Isoquinoline Analogs ~1000 85 Me -- ~5000 H Isomer 2 Isomer 1 R Calpain I IC 50 (nM)
- 28. 3,4-Dihydro-1,2-benzothiazine a-Ketoamides R’-Alkyl Groups Et Et Et Bu (diastereomers) H Bu Et CH 2 CH 2 OCH 3 Et CH(CH 3 ) 2 Et CH 2 -c-propane Et (CH 2 ) 4 CH 3 Et CH 2 Ph Et CH 2 CH 2 Ph Et CH 2 CH=CH 2 Et (CH 2 ) 3 -(imidazol-1-yl) Et (CH 2 ) 3 -(2-ketopyrrolidin-1-yl) Et (CH 2 ) 3 -(morpholin-4-yl) Et CH 2 -(pyridin-2-yl) Et CH 2 -(pyridin-4-yl) 340 50; 300 200 200 205 286 150 81 63 200 ~5000 500 195 170 240 R R’ IC 50 (nM) Wells, Bihovsky BMCL, 2004, 1035
- 29. 3,4-Dihydro-1,2-benzothiazine a-Ketoamides R’-Sulfonamides Et CH 2 CH 2 NHSO 2 CH 3 Et CH 2 CH 2 NHSO 2 (4-NO 2 -Ph) Et CH 2 CH 2 NHSO 2 (3,4-Cl 2 -Ph) Et CH 2 CH 2 NHSO 2 Ph H CH 2 CH 2 NHSO 2 Ph Et CH 2 CH 2 NHSO 2 (4-F-Ph) Et CH 2 CH 2 NHSO 2 (5-(2-pyridyl)thiophen-2-yl) Et (CH 2 ) 3 NHSO 2 Ph Et (CH 2 ) 3 NHSO 2 (4-F-Ph) Et (CH 2 ) 3 NHSO 2 (4-NO 2 -Ph) Et (CH 2 ) 3 NHSO 2 (3,4-Cl 2 -Ph) 89 47 56 40 76 29 20 35 50 50 56 R R’ IC 50 (nM) Wells, Bihovsky BMCL, 2004, 1035
- 30. General Synthesis of -Ketoamides
- 31. General Synthesis of -Ketoamide R’-Sulfonamides Chatterjee, Bihovsky, Wells BMCL , 1999, 2371
- 32. CEP-3501 PK
- 33. Profile of CEP-3501 Calpain I IC 50 7 nM Molt-4 IC 50 0.5 nM Brain Concentration 1.6 M (infused @ 22 mg/kg/h) Clearance 144 mL/mg/kg Solubility 0.22 mg/mL Gerbil global ischemia 85% reduction in spectrin breakdown Mini-Ames Test Negative (Mol. Wt. = 444)
- 35. Acknowledgements Medicinal Chemistry Ron Bihovsky Sankar Chatterjee Manoj Das Bruce Dembofsky Derek Dunn Bethany Freed Zi-Qiang Gu Mohamed Iqbal Kurt Josef James Kauer John Mallamo Patricia Messina Ming Tao Rabindranath Tripathy Gregory Wells Biochemistry Mark Ator William Biazzo Donna Bozyczko-Coyne Satish Mallya Beth McKenna Terry O’Kane Shobha Senadhi Molecular Biology Diane Lang Sheryl Meyer Chrysanthe Spais Pharmacology Lisa Aimone Richard DiRocco Bruce Jones Val Marcy Matthew Miller Jeffrey Skell Jeffry Vaught SmithKline Beecham Wayne Bowen Gregory Gallagher John Gleason Jackie Hunter William Kingsbury Gordon Moore Israil Pendrak