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SZV-1287: A new drug candidate.
The background and designing principles
Péter Mátyus
Semmelweis University
Budapest
DRUG INNOVATION: high-cost, risky business a challenging job…
Challenges for discovery:
- Complexity of pathomechanisms
- Quality of compounds
- Dogmas and Taboos (are not field-specific…)
(the list is far from being complete…)
The (sad) fact:
The chance to find a new drug is worse than
to find a needle in a haystack
Some Fundamentals of Drug Discovery
What disease?
What target(s)? (Single vs Multi…)
What molecular features? (P1-….Pn)
What strategy to design in and optimize the features?
What screening and selection strategy?
Disease and Aim:
Novel anti-inflammatory agents
Why Inflammation?
i) There are many types of primary and secondary
inflammation with acute and chronic outcomes;
Inflammation might be a trigger or a consequence.
ii) Anti-inflammatory agents affecting common elements
of inflammatory pathomechanisms might have broad
applications. (Possible) relation to other diseases (PAIN!)
iii) Many inflammatory diseases represent unmet medical
needs.
The Target:
Semicarbazide-Sensitive Amine Oxidase (SSAO)
Copper–containing, SSAO (EC 1.4.3.6)
FAD–containing AO
MAO
PAO
EC 1.4.3.4
intracellular enzymes
inhibited by clorgyline (A),
pargyline, l-deprenyl (B)
TPQ–containing AO
Diamine
oxidase
AOC1
Retinaspecific AO
AOC2
LTQ–containing AO
VAP-1
AOC3
Lysyl oxidase
LTQ: lysine tyrosylquinone
VAP-1: vascular adhesion protein-1
- an adhesion protein with SSAO activity
Metabolism of mono-, di- and polyamines
Multifunctional nature of VAP-1
Involvement in inflammation
- Leukocyte migration
- SSAO activity
Natural substrates
methyl amine
aminoaceton
↓
toxic aldehydes
S. Jalkanen et al. Arterioscler Thromb. Vasc. Biol. 28, 8-26 (2008)
A novel drug candidate based on
SSAO/VAP-1 + COX inhibition
Novel Designing Strategy
(P. Mátyus)
To achieve multiple mode of action:
combination of VAP-1 + COX inhibition through metabolic
activation of an active prodrug:
i) SSAO inhibition by the parent compound
ii) By its biotransformation to get a COX inhibitor
Screening system
- (Basic) Anti-inflammatory effect, activity in vivo: K. Gyires
To explore multiple mode of action, evaluation of
therapeutic values:
- Activity in neuropathy, Zs. Helyes et al
SZV-1287. The concept: MAMUT* approach
N
O
N
OH
biotransformation
SZV-1287
Inhibition of SSAO per se
N
Safe, no mutagenicity
O
O
OH
oxaprozin
cyclooxygenase (COX) inhibitor
(once daily)
*Metabolism-Activated Multi-Targeting
A new strategy: Chasing the MAMUT!
The concept of metabolism activated multi-targeting (‘MAMUT’) is based on
combination of synergistic effects of the parent drug and its active metabolite(s).
Drug
T1
Metabolite
T2
Disease curing
Mátyus and Chai, ChemMedChem 2015
How to discover drugs for the treatment of diseases with complex
pathomechanisms?
Conclusion: Consider new ways
1. The key word: Multi
Target selection and designing principles
- Focus on Multi-Target approaches (traditional)
synergistically active parent + metabolite(s) (MAMUT)
2. Break the dogmas and taboos
(consider creativity vs HTS)
see, C Chai and P. Matyus, Fut Med Chem, 2016
3. Work in a Multi-cultural environment
(in both disciplinary and geographic meanings…)
Thank you for your attention!
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