Poster about the new drug candidates for depression

1. Novel ligands acting as SERT blockers and dopamine D2 receptor partial agonists
with therapeutic potential for treatment of mood disorders and their comorbidities
Marcin Kołaczkowski1, Monika Marcinkowska 1, Adam Bucki 1, Joanna Śniecikowska 1, Maciej Pawłowski 1,
Grzegorz Kazek 1,Agata Siwek 1, Anna Wesołowska 1, Magdalena Jastrzębska-Więsek 1, Anna Partyka 1,
Paweł Mierzejewski 3, Przemyslaw Bienkowski 3
1Faculty of Pharmacy, Jagiellonian University Medical College, Cracow, Poland; 2Adamed Ltd., Pieńków, Poland
3Institute of Psychiatry and Neurology, Warsaw, Poland
marcin.kolaczkowski@uj.edu.pl
Compd ARYL n
% act. at 1E-06 M
SERT D2 5-HT7 5-HT1A M3 hERG
1 0 100 97 94 97 1
2 0 98 97 95 99 10 6
3 0 98 97 94 97 0 12
4 0 100 99 96 100 10 11
5 0 98 98 97 98 8 8
6 0 99 99 99 100 8 12
7 0 99 100 100 99 3 9
8 0 100 100 102 99 10 0
9 2 99 99 88 99 4
10 2 101 99 87 100 9
11 2 101 100 90 98 9
12 2 101 100 90 97 0 3
13 2 101 101 93 100 11
15 2 101 100 89 99 11
16 2 101 100 92 99 10 19
Target pKi
SERT 8.2
D2 8.4
5-HT7 7.0
5-HT1A 7.7
M3 <6
5-HT2C <6
hERG <6
SERT
9
8
5-HT7 D2
7
6
5
Selected in vivo data for ADN-3662
References
Porsolt’s forced swim test in mice 1.25
Tail suspension test in mice 0.312
Porsolt’s forced swim test in rats 1
Four-plate test in mice 0.312
Expression of saccharine self-administration in rats 3
Vogel’s conflict drinking test 1
Reversal of haloperidol-induced deficits in
saccharine self-administration in rats 1
Catalepsy in rats >100
Sedation in rats >100
Disruption of social behavior in rats >30
350
300
250
200
150
100
50
300
250
200
150
100
50
Test procedure MED mg/kg
0.0 mg/kg 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg
ADN 3662 dose
Studies were financed by Adamed Ltd, Pieńków, Poland and National Center for Research and Development (NCBiR), Warsaw, Poland
Mood disorders
Chemical structure of the lead molecule ADN-3662
Saccharine self-administration MED = 3 mg/kg
Reversal of haloperidol-induced deficits in saccharine self-administration
active dose = 1 mg/kg
 Mood (affective) disorders are a wide and heterogeneous group of medical
conditions including unipolar and bipolar depression, mania or substance-induced
mood disorders.
 Their typical comorbidities include eating disorders, anxiety disorders or drug
addiction.
 Anhedonia and affective flattening are also major features of negative
symptoms of schizophrenia [1]
 Selective serotonin reuptake inhibitors (SSRI) acting through blockade of
serotonin transporter (SERT) are a frequently-employed therapeutic options in
various affective disorders [2].
On the other hand, dopamine D2 receptor partial agonists (e.g. aripiprazole),
developed primarily as novel antipsychotic drugs, have attracted increasing
interest also as promising mood modulating agents [3] and proved synergy
with SSRIs [4,5].
 Nevertheless, the therapeutic efficacy of current drugs remains limited and
mood disorders present numerous unmet needs.
Series of novel arylsulfonamides
We designed and synthesized a novel series of arylsulfonamide derivatives,
preferentially targeting 5-HT7 receptors
 The group containing over 300 compounds was protected by an international patent
application WO2012035123 [6]
 General formula of the subset simultaneously targeting 5-HT7 as well as SERT, D2,
and 5-HT1A receptors is presented below:
D2/5-HT1A
SERT 5-HT7 receptor
In vitro profile of ADN-3662
 Significantly active in well validated mood deficit model
 Active in a model of secondary negative symptoms
 Active in other well-recognized models of mood deficits
 Additional anxiolytic effects
Very wide therapeutic window – unwanted activities (catalepsy,
sedation, memory imparement) not observed up to doses 10-100x
higher than the effective ones.
No activities associated with side-effects: anticholinergic properties,
hERG blockade etc.
Pharmacological profile of ADN-3662 warrants its further
development in the treatment of mood deficits and related
comorbidities
 Series of arylsufonamide derivatives displayed strong SERT, D2, 5-HT7 and 5-HT1A
receptor affinity with reduced activity at undesirable molecular targets, notably M3
receptors and hERG channels
 Based on in vitro and in vivo data compound 12 was chosen as the lead molecule for
further evaluation. It’s code name is ADN-3662
Blockade of SERT and 5-HT7R as well as
partial agonism at D2R and 5-HT1AR
provide synergistic effects in mood improvement
Series of arylsulfonamide derivatives was designed
to specifically interact with SERT and 5-HT7 receptors
 Crucial role of arylsulfonamide moiety for interaction with 5-HT7 binding sites
 Sulfonamide oxygen atoms form specific H-bonds with Arg7.36 side chain
 Aryl moiety penetrates hydrophobic pocket in region of transmembrane helices
(TMH) 1, 2 and 7
 Tetrahydropiridineindole (THPI) moiety provides affinity for serotonin
transporter (SERT) anchoring at Asp98 and having hydrophobic contacts with
Tyr176, Phe95 and Val343
 Arylsulfonamide group additionally stabilises the complex by H-bond with
Trp103 and cation-pi contact with Arg104
 Structures and in vitro data for the most interesting examples are collected in Table 1:
[1] Der-Avakian A, Markou A. Trends Neurosci. 2012 Jan;35(1):68-77
[2] Blier P, El Mansari M., Philos Trans R Soc Lond B Biol Sci. 2013 Feb 25;368(1615):
20120536.
[3] Brown R, Taylor MJ, Geddes J. Cochrane Database Syst Rev. 2013 Dec 17;12:CD005000
[4] Worthington JJ, 3rd, Kinrys G, Wygant LE, Pollack MH. Int Clin Psychopharmacol 2005;
20(1): 9-11..
[5] Sheffrin M, Driscoll HC, Lenze EJ, et al. . J Clin Psychiatry 2009; 70(2): 208-13
[6] Kolaczkowski, M.; Kowalski, P.; Jaskowska, J.; Marcinkowska, M.; Bucki, A.; Wesolowska, A.;
Pawlowski, M.; ‘Arylsylfonamides for the treatment of CNS diseases’ – international patent
application, priority date: 2010.09.17, international filing date: 2011.09.16, publication date:
2012.03.22. WO 2012/035123
pKi
5-HT1A hERG
M3 5-HT2C
Molecular modeling showed also complementarity
with D2 and 5-HT1A receptors
5-HT1A D2 receptor
5-HT7 SERT
4
0.0 mg/kg 1.0 mg/kg 3.0 mg/kg 10.0 mg/kg
ADN 3662 dose
0
Responses/30 min.
inactive lever
active lever
*
**
0
Responses/ 30 min.
left lever
right lever
**
 Sulfonamide oxygen atoms interact with Asn7.39 while aryl moiety interacts
with aromatic cluster formed by Tyr2.64 and Trp7.40 in 5-HT1A binding sites
 The NH group of THPI moiety stabilises the complex with D2 receptor by
forming additional H-bond with Ser5.42