11/4/2008. Presentation s Title The Scripps Research Institute Group. Efficiency of Multi-Target Drug Design in Medicinal Chemistry

Transcription

1 The Scripps Research Institute Group Efficiency of Multi-Target Drug Design in Medicinal Chemistry Presentation s Title Prof. Ed Roberts (PI) Govardhan Cherukupalli Caterina Zoni Angelica Gonzalez Miguel Guerrero The Scripps Research Institute One molecule one target Despite the advances in technology, the number of successful drugs has not increased appreciably during the past decade 1

2 Problems with Current Drug Design Strategy Gleevec/Glivec Kinase Binding Affinities Many efficient, marketed drugs are PROMISCUOUS!! Examples of drugs affecting many targets simultaneously (Gleevec, SAIDs, Salicylates) Promiscuous binding is considered to be a problem in the design and development of new drugs against a given disease. Promiscuity in molecular recognition is not all bad news Scientists are taking advantage of the emerging 'promiscuous binding' or 'multi-target approach' in medicinal chemistry. Multiple Molecules is An Evolutionary Success Story Combinatorial therapy is used increasingly to treat many types of diseases, such as AIDS, cancer Snake and spider venoms are both multi-component systems Plants employ batteries of various factors to fence off pathogenic attack Traditional medical treatments often use multi-component extracts of natural products Single targets might have back up system against a single drug therapy Multi-Target Directed Drug Design Approach One Compound that modulates two protein targets is often better than 2 compounds modulating one protein target each. Simon Frantz is the editor for ature Reviews Drug Discovery 2005 Forget drugs carefully designed to hit one particular molecule a better way of treating complex diseases such as cancer may be to aim for several targets at once 2

3 Rationale for Multi-Target Drug Design The total cost of one drug to market exceeds $800M. Taking 2 individual drugs to market for combinatorial therapy use increases risk and costs. Two sets of synthesis, costs of 2 compounds in production, eed to evaluate 2 sets of PK, Toxic, safety data in animals and humans. Investigate in detail any potential Drug-Drug interactions, metabolism/metabolites, relative rates of metabolism, clearance. eed to establish relative amounts of compounds at the site(s) of action Multi-Target Directed Drug Design Approach Multi-target drug is likely to produce a drug interacts with lower binding affinity than a single target Low affinity drug is apparently not disadvantage since they might also have lower prevalence and a reduced range of side effects Example: Hypertension Single Drug Therapy Low efficacy of single drug therapy even at high doses Poor patient compliance and tolerance due to side effects seen at high doses Combination Therapy Low doses of 2 or more medications. more effective than higher doses of any single medication due to complementary mechanisms. Better Tolerance/Compliance lower rate of adverse effects seen in low dose ranges TREDS in Pharmacological Sciences; 26, ,

4 Hypothesis One Compound that modulates two protein targets is often better than 2 compounds modulating one protein target each Our hypothesis is the synthesis of a single chemical entity, a single medicine, able to modulate multiple targets simultaneously to increase patients compliance and decrease dose/side effects of taking two drugs. Diseases Benefit from Multi-Target Approach Cancer Multiple Sclerosis Pain Asthma Diabetes Arterial Hypertension eurodegenerative Disorders Alzheimer s, Parkinson s eurodevelopmental Disorders Autism, ADHD Efforts Towards Dual Acting Medications CCK and Opioids Design and synthesis of single entity with dual pharmacological profile as Cholecystokinin antagonists and opioid agonists for the treatment of chronic (cancer associated) pain This work was Scripps Research Institute) Cholycystokinin (CCK) is a gastrointestinal peptide hormone also found in high concentrations in the brain CCK belongs to a class of peptides that acts both as gut hormones and as central neurotransmitters CCK interacts with at least two types of receptors: CCK-1 and CCK-2 Papaver somniferum 4

5 Opioids CCK and Opioids The most established clinical treatment to patients with chronic pain. Three opioid receptor subtypes cloned so far: Mu (µ), Delta ( ), Kappa ( ) Identification in the CS and periphery Both CCK and opioid receptors are members of the class of the superfamily of GPCRs CCK can be considered as an endogenous ATIOPIOID because attenuates analgesia induced by administration of opioids. Accordingly, CCK antagonists enhance morphine antinociception The development of tolerance to the antinociceptive effect of morphine may involve an upregulation of CCK. Accordingly, CCK antagonists reverse the development of tolerance to morphine in rats Opioid agonists and CCK antagonists act synergistically when administered together (An antagonist of CCK-1 receptor alleviates pain in humans when given in conjunction with a morphine derivative) * Our hypothesis is that a molecule with these characteristics would be useful in treatment of neuropathic pain states. Simpson, K., et al. Proceeding 10th World Congress on Pain, San Diego, CA, 479,1443, 2006 Possible strategies for Multi-Target Design A) Tethering (cut and paste) B) Common Template Sharing Tethering Strategy Identification of functional groups on the first molecule, that is known to tolerate some substitutions from Structure Activity Relationship (SAR) prospective Linking this functional group to a similar site on the second molecule. The linkage has to be easily broken down into the body (e.g Amide or ester linkage) 5

6 Tethering Strategy A) CCK antagonists Tethering Strategy B) Opioid agonists O H O H O H O H Devazepide CCK-1 selective antagonist L-365,260 CCK-2 selective antagonist AR-M 390 selective agonist Fentanyl selective agonist selective mu agonist Tethering Strategy Possible Opioid agonist/cck antagonist hybrids Identification of functional groups on the molecule of one ligand, that is known to tolerate some substitutions by other related functional groups, and linking these to a similar site on the second ligand molecule. Research QU Design and Synthesis of Serotonin re-uptake inhibitors & 5-HT 1B/1D antagonists for treatment of repetitive behavior aspect of autistic spectrum disorders 6

7 What is Autism?? Autism is a poorly understood complex neurodevelopmental disorder generally appears before the age of 3 and lasts throughout person's lifetime Autism prevalence increases significantly (from 1: 10,000 in the mid 90 s to 60: 10,000 as of 2007) making it more common than pediatric cancer, diabetes, and AIDS combined. It occurs in all racial, ethnic, and social groups and is four times more likely to strike boys than girls. The statistics imply the presence of approx individuals in Qatar either already diagnosed or yet to be diagnosed. Prevalence of autism Characteristics of autism Autism characterized by 3 main domains: 1. Dysfunction in social interaction skills 2. Impairment in communication/language 3. Repetitive behaviors Diagnostic Symptoms: Resistance to change (rigid routine) Difficulty expressing needs, delayed speech Prefer to be alone, difficulty socializing Tantrums Lack of affection o (or little) eye contact Obsessive play with restricted interests o fear of Danger on-responsive to verbal cues, acts deaf Repetitive behaviors Repetitive behaviors Repetitive behaviors, is shared by both patients with autism as well as obsessive compulsive disorder (OCD) The recurrent impulses (obsession) and patterns of behavior (compulsions) interfere with simplest tasks of daily living, and negatively affect the individual s life and relationship with others Thus, finding a therapeutic target to reduce or modulate repetitive behaviors is urgently needed 7

8 Serotonin and autism Mechanism of SSRI The neurotransmitter serotonin (5-HT) is known to play a vital role in the etiology and/or pharmacotherapy of repetitive and social behaviors Selective serotonin reuptake inhibitors (SSRIs) such as (Prozac), and (Zoloft) have proven efficacy in treating depression as well as autistic and OCD symptoms, including repetitive behaviors Despite its proven efficacy, it takes 2-3 weeks for an SSRI to become therapeutically efficient (major drawback), which decrease patient compliance and increase the anxiety level OUR HYPOTHESIS Known compounds Both SSRIs and 5HT 1B/1D autoreceptors are key player currently involved in the pharmacotherapy of repetitive behaviors. Co-administration of an SSRI and a 5HT 1B/1D antagonist would simultaneously block the inhibitory autoreceptors, reducing the time required for therapeutic action, and enhancing SSRI efficiency HYPOTHESIS: To utilize the above strategy and combine the pharmacological profiles of SSRIs and 5HT 1B/1D antagonist in one molecule(s) to increase patients compliance and decrease dose/side effects of taking two drugs. 8

9 Potential Hybrids using the Tethering Technique Research Milestones Milestone 1: Design a small library of molecules with dual pharmacological profile (5-HT reuptake inhibition and 5HT 1B/1D antagonism) The rationale is based on literature information to first identify the chemical structure features or scaffold believed to be responsible of the desired pharmacological effect. Then, linking these motifs to scaffolds/templates through an appropriate chemistry using the tethering strategy. Literature search again to confirm the novelty of the proposed chemical structures will be conducted. Research Milestones Research Milestones Milestone 2: Synthesis of the proposed 4 series of compounds The approach to the synthetic objectives will be carried out dynamically, in successive iterative cycles of design, synthesis, biological evaluation, analysis of results, and continuous correction of objectives (biodirected synthesis) till we identify our lead molecule. Thereafter, structure-activity relationships (SARs) will afford insights for obtaining further molecules with better dual activity. The synthetic schemes of the proposed representative compounds will be executed according to the traditional and modern synthetic chemistry techniques. Milestone 3: In Vitro Pharmacological evaluation of the synthesized compounds In vitro pharmacological evaluation is the third step after design and synthesis in our successive cycle of biodirected synthesis. Evaluation of the receptor/transporter binding affinities as well as their functional activity will be conducted through the following assays: 1. Radioligand binding assay to determine the binding affinities (K i ) at 5- HT 1B and 5-HT 1D receptors. 2. Radioligand binding assay at 5-HT transporter to determine the binding affinities (K i ) at 5-HT transporter. 3. Functional assay to determine the ability of the tested compounds to antagonize 5-HT- 1B and 5-HT 1D receptors. 4. Functional assays to determine the ability of the tested compounds to inhibit the 5-HT release from 5-HT- transporter. 9

10 Research Milestones Milestone 4: Measurable Hypothesis Our initial criteria for the lead compound are to achieve complete radioligand displacement with binding affinity (K i ) less than 100 nm at both receptors Our criteria for the lead compound are to have a drug-like character and an inhibition effect at both 5-HT- 1B/1D and 5-HT transporter in a concentration dependent manner with IC50 <100 nm. Lead to Drug optimization will be considered in a further research 10