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: h.stark@pharmchem.uni-frankfurt.de
H. Stark
Stark-Lab
Biogenic Amines
Dopamine
Histamine
Lipids
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
The Magnificent Seven
NH2
HN
N
Four histamine receptor subtypes (H1 – H4)
Original source:
七人の侍
Shichinin no samurai
2
Histaminergic System

NH2
HN
N
Histamine
Modulator
of (patho)physiological effects
in CNS and periphery
Tuberomammilary nucleus
Histamine receptors
GPCR Class A
H1
H2
H3
Allergic reactions
Sleep / wake cycle
Gastric
acid secretion
Neurotransmission
H4
Inflammatory
processes
5
Schematic Histaminergic Innervation
L-Histidine
H3 Heteroreceptors
(ACh, DA, 5-HT, NA, NANC ...)
Glia cells
Histamine
Gi/o
-
H3
N-Methylhistamine
HMT
Histamine
H4
H1
6
IP3
DAG
Modulation of
 energy metabolism
 blood circulation
cAMP  sleep / waking state
H2
3
Therapeutic Targets of
Histamine H3 Receptor Antagonists
Schizophrenia,
depression
Epilepsy
Neuropathic pain
Sleep-wake disorders
(narcolepsy)
hH3R
Cancer
Cognition disorders
(Alzheimer´s D, ADHD)
Allergy
Migraine
Obesity
7
Histamine H3 Receptor Antagonists
In vitro
In vivo
Ki
ED50 p.o.
S
N
[nM]
N
H
[mg/kg]
N
N
H
N
2.2
Thioperamide
1
O
N
H
N
FUB 465
N
H
Proxyfan
580
0.26
O
N
O
N
H
Ciproxifan
O
19
0.5
(>10)
0.14
(protean
agonist)
inverse
agonist
8
4
Synthesis of Keto Derivatives
4-(3-Phenoxypropyl)-1H-imidazole Structure
O
C
N
OH
+
HO
Mitsunobu
reaction
H+
R1
R2
N
CPh3
N
4/5 steps
N
H
NaH
O
C
N
OH
+
H+
O
C
O
C
R1
O
R2
N
R2
NOH
N
F
R1
R1
R2
N
H
CPh3
R1
2
R
CH3
CH3
CH3
2-CH3 3-CH3 2-F
(CH2)1-5-H
CH3
CH3
C2H5
H
2-CF3 OCH3 2-F
Ph
2-F
etc.
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
Ki
ED50 p.o.
S
N
[nM]
N
H
[mg/kg]
N
N
H
N
10
FUB 465
N
H
Proxyfan
N
H
1
O
N
H
N
N
2.2
Thioperamide
580
0.26
O
O
Ciproxifan
O
19
0.5
(>10)
0.14
(protean
agonist)
inverse
agonist
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
Correct Responses (%)
N
H
Duration Stimuli
90
80
*
70
60
50
13
0.50 s
0.25 s
* P < 0.05
Control
Ciproxifan
(3 mg/kg, i.p.)
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
S1
W
Placebo
Ciproxifan
0.15 mg/kg
0.3 mg/kg
0.7 mg/kg
2 mg/kg
0
1
2
3
PS = paradoxical sleep
S1 = light slow wave sleep
Ciproxifan - J. Pharmacol. Exp. Ther. 1998, 287, 658.
t (h)
4
S2 = deep slow wave sleep
W = wakefullness
Pitolisant - J. Pharmacol. Exp. Ther. 2007, 320, 365.
Receptor Profile of Ciproxifan
O
N
10
9.3 9.4
9.3
9
Receptor assays:
H1
H2
H3
H3
H3
H3
H3
H4
O
N
H
8.4
8
7.2
M3 GP ileum
1D R aorta
7
5.7
6
5
5.4 5.4
4.9
<4.7
<5.7<5.7 5.6
4.9 <5.0 4.9
4
3
H1 H2 H3 H3 H3 H3 hH3 M3 1D 1 div. 5 - H T
R GP NHAMe NA
4
1B 2A 3
hH4

16
GP ileum
GP atrium
R synaptosomes
GP ileum
M NMeHA liberation
M NA liberation
H CHO
H CHO
1
GP atrium
5-HT1B GP inguinal artery
5-HT2A R tail artery
5-HT3 GP il. plex. myenter.
5-HT4 R oesophagus
CYP450 H placental
mikrosomes
CYP450
GP
R
M
H
= guinea-pig
= rat
= mouse
= human
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
Val122

Ala119

Ciproxifan
Human
Ala122
Ciproxifan
Thr119
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
N
H
FUB
372
Carbonyl
displacement
CH3
N
O
N
H
hKi = 3.6 nM (IPX)
ED50 = 0.20 mg/kg
UCL 1791
Imidazole
Replacement
(CyP450 interaction ?)
hKi > 30 nM
(MeHA)
ED50 = 0.24 mg/kg
O
CH3
N
O
New Lead
18
Holger Stark
9
Extended Blue Print
Histamine H3 Receptor Antagonists
19
Histamine H3 Receptor Antagonists
Imidazole-based
Non-imidazole-based
O
O
N
Cl
N
FUB 649
O
HN
N
Ciproxifan
N
S
N
N
N
H
Thioperamide
HN
N
ABT-239
N
N
H
N
O
CH3
H
H
O
N
H
N
N
GT-2331
O
JNJ-20281457
GSK189254
O
Polar group
and/or
1st basic
moiety
Spacer
Central
core
2nd
basic moiety
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
 H3 Antagonists – HMT Inhibitors
Ki = 0.22 nM
 H3 Antagonists – HMT / ACh / BuCh Inhibitors
Cowart, M. et al. Poster P49,
34th Meeting of EHRS, Bled/Slovenia, 2005.
 H3 Antagonists – M2 Antagonists
 H3 Antagonists – Leukotrien Antagonists
 H3 Antagonists – SSRI
 H3 Antagonists – neuroleptics etc.
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
1. Cleavable
Konjugate
Fluorophore F2
H3
Cleavable chain
F2
H3
Chain
F2
H3
F2
2. Konjugate
3. Additive
Compounds
4. Integrative
Compounds
H3
F2
Drug Disc. Today 2004, 9, 736.
11
Synthetic Pathways
to Final Fluorescence Compounds
NH
Br
i
OH
N
ii
OH
Cl
N
iii
R
R
HO
N
O
R = NO2, CN, phenyl-CN, OH
2
R
O
R=
=N
O
R=
R=C
N
NH2
H
iv
OH
v
NH2
N
N
ph
en
ylp-C
v
N
O
O
N
O
NH2
N
Cl
O2N
O
NO2
vi
N
O
vi
F
NO2
vii
N
NO2
X1
N
O
X2
N
O N
NO2
N
O
NO2
X2 = NH, CH2-NH, phenyl-CH2-NH, O
X1 = NH, CH2-NH
Nitrobenzofurazans
Sanger´s derivatives
hH3 Binding Affinities
and Physicochemical Properties
X
Fluorophore
N
O
ClogP
Ex.
Em.
max [nm] max
0.066
5.63
481
531
0.572
5.10
415
533
-C6H4-CH2-NH-
0.706
7.04
452
531
-CH2-NH-
0.603
5.16
396
496
0.140
5.70
396
449
0.048
5.00
397
527
X
Fluorophore
-NH-CH2-NH-
N
O N
NO2
-NH-
O2N
-O-
hH3 Ki
[nM]
NO2
ChemMedChem 2007, 2, 708-716
12
Details for ST-688
NO2
hH3 Ki = 48 ± 13 pM
O
N
O
ED50 = 0.96 mg/kg p.o. (mice)
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
N
(INN: Pitolisant (formerly: tiprolisant); NME; orphan drug)
O
Cl
Clinical Phase IIb (DBPCX) (n=12)
Photosensitive Epilepsy – therapy resistant
Patient
20 mg BF-2.649
26
Holger Stark
40 mg BF-2.649
60 mg BF-2.649
(different
co-medications)
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
3
4
3
O
12
Cl
(BF-2.649, pitolisant)
40 mg/d - 22 patients
28
14
Compounds in Clinical Development
Phase II
EDS in narcolepsy (HARMONY I & II)
+ Narcolepsy
etc.
Phase III
N
O
EDS in sleep apnoe syndrome (HAROSA I & II)
Cl
Pitolisant
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
GSK 239512
NHCH3
N
Pro-cognitive effects in schizophrenia
O
N
Pro-cognitive effects in Alzheimer
ABT-288
Pro-cognitive effects in schizophrenia
JNJ-39220675
Allergic rhinitis
PF-3654746
Allergic rhinitis
29
Waking state
Cognition
Periphery
EDS =
Excessive
Daytime
Sleepiness
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. Hütter
• K. Isensee  K. Sander
u.a.
Freie Universität Berlin
•
•
•
•
•
•
Prof. W. Schunack
Prof. H. H. Pertz
Dr. J. Apelt
Dr. S. Graßmann
Dr. G. Meier
T. Rudolf u.a.
INSERM, Paris, and
Bioprojet, Paris/Rennes, France
•
•
•
•
•
Prof. J.-C. Schwartz
Dr. J.-M. Arrang
Dr. J.-M. Lecomte
Dr. S. Morissett
X. Ligneau u.a.
bioprojet
Martin Luther-Universität University College London, U.K.
Halle-Wittenberg
• Prof. Dr. W. Sippl
• Dr. B. Schlegel
• Prof. C. R. Ganellin
Europäische Union (BIOMED I, II)
Fonds der Chemischen Industrie, Verband der Chemischen Industrie
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