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Histamine H Receptor Antagonists Histamine H3 Receptor Antagonists from Bench to Bedside Holger Stark XVIIIth Summer School on Medicinal Chemistry Rio de Janeiro/Brazil, January 23-27, 2012 Institut für Pharmazeutische Chemie Biozentrum, Johann Wolfgang Goethe-Universität E-Mail: [email protected] H. Stark Stark-Lab Biogenic Amines Lipids Dopamine Histamine NMDA Sphingosine AA 1 Content Introduction histamine receptors . Subtypes . Functions Histamine H3 receptor antagonists . From imidazole to non-imidazole compounds . Pharmacological tools . Clinical candidates – clinical trials Summary 3 NH2 HN The Magnificent Seven N Four histamine receptor subtypes (H1 –H4) Original source: 七人の侍 Shichinin no samurai 2 NH2 HN Histaminergic System N Histamine . Modulator of (patho)physiological effects in CNS and periphery Tuberomammilary nucleus Histamine receptors GPCR Class A H1 H2 H3 H4 Allergic reactions Gastric Neurotransmission Inflammatory Sleep / wake cycle acid secretion processes 5 Schematic Histaminergic Innervation L-Histidine H3 Heteroreceptors (ACh, DA, 5-HT, NA, NANC ...) - Glia cells Histamine Gi/o - N-Methyl- H3 histamine Histamine HMT H4 Modulation of H H1 2 energy metabolism blood circulation IP3 DAG cAMP 6 sleep / waking state 3 Therapeutic Targets of Histamine H3 Receptor Antagonists Schizophrenia, depression Epilepsy Neuropathic pain Sleep-wake disorders hH R (narcolepsy) 3 Cancer Cognition disorders Allergy (Alzheimer´s D, ADHD) Migraine Obesity 7 Histamine H3 Receptor Antagonists In vitro In vivo S Ki ED50 p.o. [nM] [mg/kg] N N H N Thioperamide 2.2 1 N H N O N FUB 465 580 0.26 H N O N 19 (>10) (protean H Proxyfan O agonist) N O inverse N Ciproxifan 0.5 0.14 agonist H 8 4 Synthesis of Keto Derivatives 4-(3-Phenoxypropyl)-1H-imidazole Structure O C R1 Mitsunobu O N reaction OH + + HO H C 1 2 R N R CPh N O 3 R2 N 4/5 steps H+ H O NaH NOH C C 1 R1 R N OH N + F O 2 R2 R N N H CPh3 1 R CH3 CH3 CH3 (CH2)1-5-H CH3 CH3 C2H5 Ph 2 etc. R 2-CH3 3-CH3 2-F H 2-CF3 OCH3 2-F 2-F J. Med. Chem. 2000, 43, 3335; J. Med. Chem. 2000, 43, 3987; Bioorg. Med. Chem. Lett. 2000, 10, 279. Histamine H3 Receptor Antagonists In vitro In vivo S Ki ED50 p.o. N N [nM] [mg/kg] H N Thioperamide 2.2 1 N H N O N FUB 465 580 0.26 H N O (protean N Proxyfan 19 (>10) H O agonist) N O inverse Ciproxifan 0.5 0.14 agonist N H 10 5 Chemical Space Text durch klicken hinzufügen Hier steht die Copy 11 Nat. Rev. Drug Disc.2006,5, 993–996. Blue Print Histamine H3 Receptor Antagonists (Ciproxifan) old new 12 6 H O Five-Choice Task (Rat) N O N H 90 Duration Stimuli 0.50 s 0.25 s 80 * P < 0.05 * 70 60 Correct Responses (%) 50 Control Ciproxifan (3 mg/kg, i.p.) 13 J. Pharmacol. Exp. Ther. 1998, 287, 658-666. Rodent Models for Preclincal Testing 14 Esbenshade et al. Mol. Interv. 2006, 6, 77-88 7 Hypnograms of Ciproxifan p.o. in Cats PS S2 Placebo S1 W Ciproxifan 0.15 mg/kg 0.3 mg/kg 0.7 mg/kg 2 mg/kg 0 1 2 3 t (h) 4 PS = paradoxical sleep S2 = deep slow wave sleep S1 = light slow wave sleep W = wakefullness Ciproxifan - J. Pharmacol. Exp. Ther. 1998, 287, 658. Pitolisant - J. Pharmacol. Exp. Ther. 2007, 320, 365. Receptor Profile of Ciproxifan O Receptor assays: H1 GP ileum N H2 GP atrium O 10 H3 R synaptosomes 9.3 9.3 9.4 N H3 GP ileum H H M NMeHA liberation 9 3 8.4 H3 M NA liberation H3 H CHO 8 H4 H CHO 7.2 M3 GP ileum 7 1D R aorta 1 GP atrium 5.7 5-HT1B GP inguinal artery 6 <5.7<5.7 5.6 5.4 5.4 5-HT2A R tail artery 4.9 <5.0 5-HT GP il. plex. myenter. <4.7 4.9 4.9 3 5 5-HT4 R oesophagus CYP450 H placental 4 mikrosomes GP = guinea-pig 3 R = rat H1 H2 H3 H3 H3 H3 hH3 M3 1D 1 div. 5 - H T CYP450 NMe M = mouse R GP NA 1B 2A 34 HA hH4 H = human 16 J. Pharmacol. Exp. Ther. 1998, 287, 658; Mini Rev. Med. Chem. 2004, 4, 965 8 Binding Model of Ciproxifan at Human and Rat H3 Receptors TM3 Rat Human 122 122 Val Ala Ciproxifan Ala119 Thr119 Ciproxifan Ciproxifan Influence beyond binding pocket „humanised“ rat H3 receptor shows similar binding properties like human H3 receptor 17 Br. J. Pharmacol. 2000, 131, 1247 Bioorg. Med. Chem. Lett. 2001, 11, 951 Non-Imidazole H3 Receptor Antagonists O CH3 N O hKi > 30 nM N FUB (MeHA) H ED = 0.24 mg/kg Carbonyl 372 50 CH displacement 3 N O hK = 3.6 nM (IPX) N i H ED = 0.20 mg/kg UCL 1791 50 Imidazole Replacement CH3 N O (CyP450 interaction ?) New Lead 18 Holger Stark 9 Extended Blue Print Histamine H3 Receptor Antagonists 19 Histamine H3 Receptor Antagonists Imidazole-based Non-imidazole-based O N O N Cl O FUB 649 HN Ciproxifan N N S N H CH3 O N N ABT-239 N O H N N JNJ-20281457 Thioperamide HN H O N N H GT-2331 N H N GSK189254 O Polar group and/or 1st basic Central 2nd basic moiety S p a c e r moiety core and/or liphophilic residue and / or acidic residue 20 Exp. Opin. Investig. Drugs 2009, 18, 1519; Bioorg. Med. Chem. Lett. 2010, 20, 1581 10 Actual Status of Compounds with Additional Functions H3 Antagonists – H1 Antagonists H3 Antagonists – NO-Releasing H3 Antagonists – H4 Ligands K = 0.22 nM H3 Antagonists – HMT Inhibitors i Cowart, M. et al. Poster P49, H3 Antagonists – HMT / ACh / BuCh Inhibitors 34th Meeting of EHRS, Bled/Slovenia, 2005. H3 Antagonists – M2 Antagonists H3 Antagonists – Leukotrien Antagonists H3 Antagonists – SSRI H Antagonists – neuroleptics etc. 3 Ki = 11 nM H3 Ligands – Radioactive elements H3 Antagonists – Fluorescence properties Bioorg. Med.Chem. Lett. 2006, 16, 1938-40. Approaches on Novel Leads with Additional Functionalities Pharmacophor H3 Fluorophore F2 1. Cleavable Konjugate H3 Cleavable chain F2 2. Konjugate H3 Chain F2 3. Additive Compounds H3 F2 4. Integrative Compounds H3 F2 Drug Disc. Today 2004, 9, 736. 11 Synthetic Pathways to Final Fluorescence Compounds NH i N OH ii N Cl Br OH iii R R HO N O R = NO2, CN, phenyl-CN, OH R= ph en 2 yl NO R -p = = -C R O v N iv H N C = v OH R NH2 NH2 N O N O N O NH2 N O O2N vi Cl NO2 F NO vi 2 vii N N O NO2 X1 X2 N O N NO2 N O NO2 O N 1 2 X = NH, CH2-NH X = NH, CH2-NH, phenyl-CH2-NH, O Nitrobenzofurazans Sanger´s derivatives hH3 Binding Affinities and Physicochemical Properties X Fluorophore N O hH3 Ki ClogP Ex. Em. X Fluorophore [nM] max [nm] max -NH- 0.066 5.63 481 531 -CH2-NH- 0.572 5.10 415 533 N NO2 O N -C6H4-CH2-NH- 0.706 7.04 452 531 -CH2-NH- 0.603 5.16 396 496 -NH- 0.140 5.70 396 449 O2N NO2 -O- 0.048 5.00 397 527 ChemMedChem 2007, 2, 708-716 12 Details for ST-688 NO2 hH K = 48 ± 13 pM O 3 i ED50 = 0.96 mg/kg p.o. (mice) N O NO2 Clog P = 5.00 (calc.) (conc. = 10-5 M (ethanol)) max = 397 nm max = 527 nm Stokes Shift = 130 nm 18F –ST-889 cf. Bioorg. Med. Chem. Lett. 2009, 19, 2172 Histamine H3 Receptor Antagonist BF-2.649 (INN: Pitolisant (formerly: tiprolisant); NME; orphan drug) N O Cl Clinical Phase IIb (DBPCX) (n=12) Photosensitive Epilepsy – therapy resistant Patient 20 mg BF-2.649 40 mg BF-2.649 60 mg BF-2.649 (different co-medications) 26 Holger Stark WO 2006084833. + Arch. Pharm. 2008, 341, 610 13 Narcolepsy Rusty, the narcoleptic Dachshund 27 Clinical Trial on Narcoleptic Patients (n=22) Change in Epworth Sleepiness Scale (ESS) (Total values of one week with standard co-medication) N O 3 4 3 12 Cl (BF-2.649, pitolisant) 40 mg/d - 22 patients 28 14 Compounds in Clinical Development + Narcolepsy Phase II Phase III etc. EDS in narcolepsy (HARMONY I & II) N O EDS in sleep apnoe syndrome (HAROSA I & II) Pitolisant Cl EDS in Parkinson´s therapy (HARPS I & II) Pro-cognitive effects in schizophrenia MK0249 EDS in sleep apnoe syndrome JNJ-17216498 Narcolepsie O Pro-cognitive effects in Alzheimer NHCH3 GSK 239512 N Pro-cognitive effects in schizophrenia O N Pro-cognitive effects in Alzheimer ABT-288 Pro-cognitive effects in schizophrenia EDS = JNJ-39220675 Allergic rhinitis Waking state Excessive PF-3654746 Allergic rhinitis Cognition Daytime Periphery Sleepiness 29 Celanire et al. Drug Discovery: From Hits to Clinical Candidates. CRC Press, 2009, pp. 103. Sander et al. Histamine H3 Receptor Antagonists go to Clinics. Biol. Pharm. Bull., 2008, 31, 2136. Summary Novel histamine H3 receptor antagonists Robust antagonist pharmacophor . Pharmacodynamic profiling (multiple targeting) . Pharmacokinetic optimization . Toxicity reduced Novel therapeutic concepts (NME, clinical phase III) . Epilepsy, narcolepsy, dementia . Late stage in clinical development Interdisciplinary and translatory research by numerous experts in their fields 30 15 Acknowledgement Johann Wolfgang Goethe-Universität Frankfurt am Main • M. Amon Y. von Coburg B.
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