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

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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 NMeHA 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 NMe 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

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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

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15 Acknowledgement Johann Wolfgang Goethe-Universität Frankfurt am Main • M. Amon  Y. von Coburg  B. Hütter • K. Isensee  K. Sander u.a. Freie Universität Berlin INSERM, Paris, and • Prof. W. Schunack Bioprojet, Paris/Rennes, France • Prof. H. H. Pertz • Prof. J.-C. Schwartz •Dr. J. Apelt • Dr. J.-M. Arrang •Dr. S. Graßmann •Dr. J.-M. Lecomte •Dr. G. Meier • Dr. S. Morissett •T. Rudolf u.a. • X. Ligneau u.a. bioprojet Martin Luther-Universität University College London, U.K. Halle-Wittenberg • Prof. Dr. W. Sippl • Prof. C. R. Ganellin • Dr. B. Schlegel

Europäische Union (BIOMED I, II) Fonds der Chemischen Industrie, Verband der Chemischen Industrie 31

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