This slides describes the concept of bivalent compounds. It improve the potency significantly by simply joining two compounds by flexible or rigid linker. PROTAC and Molecular glue is gaining lot of interest is basically an extension of this idea . My personal journey of designing dual inhibitors started in 1996, when we worked on combining Steroids with Enediyne. Later during my professional journey, we have tried to make compounds like DDP4-ACE, GyraseB-Topo4, HNE Bivalent and many other undisclosed work. My interest in this area is never weaning out. Recently, i am observing a lot of interest in RNA-PROTAC, Antibody Oligo or Aptamer Oligo conjugates. Hope to witness successful launch of a blockbuster compound form this kind of combination approach.
3. Introduction
➢For a polyvalent interaction, the avidity constant can be written as.
Kn
poly = (Kmono)αn
When α>1, in a positively cooperative interaction, the
binding of the first ligand causes a decrease in the free energy of binding for
subsequent ligands, making the interaction more favorable.
➢Main course of drug discovery: Single pharmacophoric moiety aimed at
hitting a single biological target
➢Polyvalency in the biological world is defined as the simultaneous
binding of multiple ligands to one receptor
4. General target profile for Polyvalent Therapeutics
➢ Related disease / multiple target for the same disease (Homo / Hetero dimer)
➢ Oligomeric Target
➢ Active site + Allosteric site
➢ Active site + Non specific interaction
5. Use of Polyvalent Therapeutics
➢ Related disease:
▪ Diabetes + Hypertension
▪ Hypertension + Psychotic disorder
▪ Obesity + Diabetes
▪ COPD + Lung infection
➢ Same disease Multiple Target
▪ Cancer (eGFR+vEGFR)
▪ Antmicrobial (GyraseB + TopoIV)
▪ Hypertension (ACE+ NEP)
▪ Alzheimer's (AChE + MAO)
6. GyraseB + Topo IV dual inhibtor
Quercetin Diacylglycoside
7. Example 4
Example 1
Example 2
Quinolone Oxazolidinone hybrid (EP2256120A1)
Ref: EP2256120A1 (Actelion Pharma 1st Dec 2010)
8. Huperzine
US Patent Number: US 6,472,408
UK Patent Number: GB 2,360,518
An illustration of dual site binding of a novel dimeric inhibitor
to the catalytic and peripheral sites of AChE
Dimeric Huperzine derivatives in Alzheimer's Disease
10. Life Sci 2005; 76, 1267-79
J Med Chem 2004, 47, 1290-8
Expert Opinion in Therapeutic patent 2006, 16, 1665- 72
Dimeric Artemisin derivatives as Anti cancer agent
17. Advantage
➢ Can enhance the overall affinity of the interaction by several orders of
magnitude over the corresponding monovalent interaction.
➢Can easily establish an IP position, for a fast follow on approach
➢Can be an effective weapon for multi target therapy
18. Disadvantage
➢Optimization of physicochemical and pharmacokinetic properties,
particularly to ensure a good oral bioavailability,
➢Difficult to synthesize and not so easy to identify the tethering position
➢Can only be successful in critical care and Inhalation Therapy
19. Conclusion
➢Allows combination of more than one identical or different pharmacophores
rather than the structural modification of a single one
➢Complementary pharmacological effects, and, consequently to an enhanced
efficiency in the management of that particular disease
➢Bivalency or polyvalency represents a rational approach in designing molecules
with higher affinity and avidity towards putative cancer-related biological targets.
➢A challenging but fast forward approach
➢Example of success is rare compare to conventional drug design
20. Further reading
[1] Morphy R, Rankovic Z. Designing Multiple Ligands − Medicinal Chemistry Strategies and Challenges. Curr Pharm Des 2009;
15(6): 587-600.
[2] Bolognesi ML, Rosini M, Andrisano V, Bartolini M, Minarini A, Tumiatti V, Melchiorre C. MTDL Design Strategy in the
Context of Alzheimer’s Disease: from Lipocrine to Memoquin and Beyond. Curr Pharm Des 2009; 15(6): 601-613.
[3] Martelli A, Breschi MC, Calderone V. Pharmacodynamic Hybrids Coupling Established Cardiovascular Mechanisms of
Action with Additional Nitric Oxide Releasing Properties. Curr Pharm Des 2009; 15(6): 614-636.
[4] Kim YS, Lee JH, Ryu J, Kim DJ. Multivalent & Multifunctional Ligands to β-Amyloid. Curr Pharm Des 2009; 15(6): 637-658
[5] Chow LMC, Chan TH. Novel Classes of Dimer Antitumour Drug Candidates. Curr Pharm Des 2009; 15(6): 659-674.
[6] Shrivastava A, Nunn AD, Tweedle MF. Designer Peptides: Learning from Nature. Curr Pharm Des 2009; 15(6): 675-681.
[7] Liu Z, Zhang J, Zhang A. Design of Multivalent Ligand Targeting G-Protein-Coupled Receptors. Curr Pharm Des 2009; 15(6):
682-718.
[8] Lezoualc’h F, Jockers R, Berque-Bestel I. Multivalent-Based Drug Design Applied to Serotonin 5-HT4 Receptor Oligomers.
Curr Pharm Des 2009; 15(6): 719-729.
