(11/27) Thatcher Lecture: Medicinal Chemistry and Pharmacology of MS Agents Multiple Sclerosis (MS): MS likely describes a collection of diseases, as it is based upon symptoms, of which prior to their manifestation are difficult to diagnose. Without a diagnosis, preventative and prophylactic treatment becomes difficult. A neurodegenerative disorder with a complex background, heredity alone is not a dependable affirmation for prophylactic tx. Understanding MS: An autoimmune disorder. A chronic inflammatory disease. A disrupted neuronal response - Key Aspect: Demyelination, destruction of myelin sheath by the immune disorder leading to nerve dysfunction - Position of Healthcare: There is an Unmet Need for identifying mechanisms to halt disease progression. There are failures in Compliance, where the IV first-line therapies are poorly tolerated. Interventions are dominated by Disease Modifying Therapeutics (DMTs), newer oral agents used to slow progression. Unfortunately, the DMTs are not too significant in what they offer Quick Ramble: - Glatiramer Acetate (Copaxone) o MoA: Mixture of peptides of differing size, containing 4 AA of basic myelin protein. These peptides offer an antigen to protect the myelin sheat of the neurons, acting as a decoy for attacking immune cells - Mitoxantrone (Novantrone): Can be used in SPMS. It is an antineoplastic agent also used in cancer therapy - Natalizumab (Tysabri): “Anti-Integrin” mAb, used in MS and Crohn’s. o MoA: Attempts to counteract the autoimmune aspect of the disease by preventing adhesion of lymphocytes to the vascular endothelium. IV drug given every 28 days Fingolimod (Gl): The first MS Oral drug – it was a “phenotypic” drug discovery - Discovery: Natural product derived from fungi, ISP-I (Myriocin). It was noticed to have immunosuppressant properties, inhibiting serine palmitoyltransferase, though it was toxic and poorly soluble greasy surfactant chain. Issues include: o We do not like the double bond or ketone = Sites for metabolism o We don’t like the polar head group because of the stereocenters (complex) o It lacks a chromophore so we cannot monitor it - ISP-I Optimization: It was a hit, but now we have to optimize it towards a lead o (1) Elimination of Chiral Centers (Chiral centers are hard to multiply and purify) o (2) Remove Side Chain Functionalities (Reactive, Unpredictable metabolism) o (3) Vary Chain Length (Just experimenting) § Immunosuppressant Model – Mean Survival Time (MST) Experiment in rat skin allografts. Discovered that 14-15 carbons are optimal for immunosuppressant properties. § Toxicity Experiments showed 15 carbons are more toxic than 14. o (4) Incorporation of Phenyl ring to improve ADMET and facilitate spectroscopic detection at low concentrations o (5) Vary chain length again - MoA: Prevents the release/egress of lymphocytes (and other inflammatory.mediators) from lymph nodes. Thus, these immune system components will not cross the vascular endothelium and cause damage. This mechanism does not include the serine palmitoyltransferase.
Transcript
(11/27) Thatcher Lecture: Medicinal Chemistry and Pharmacology of MS Agents Multiple Sclerosis (MS): MS likely describes a collection of diseases, as it is based upon symptoms, of which prior to their manifestation are difficult to diagnose. Without a diagnosis, preventative and prophylactic treatment becomes difficult. A neurodegenerative disorder with a complex background, heredity alone is not a dependable affirmation for prophylactic tx.
Understanding MS: An autoimmune disorder. A chronic inflammatory disease. A disrupted neuronal response - Key Aspect: Demyelination, destruction of myelin sheath by the immune disorder leading to nerve dysfunction - Position of Healthcare: There is an Unmet Need for identifying mechanisms to halt disease progression. There are
failures in Compliance, where the IV first-line therapies are poorly tolerated. Interventions are dominated by Disease Modifying Therapeutics (DMTs), newer oral agents used to slow progression. Unfortunately, the DMTs are not too significant in what they offer
Quick Ramble: - Glatiramer Acetate (Copaxone)
o MoA: Mixture of peptides of differing size, containing 4 AA of basic myelin protein. These peptides offer an antigen to protect the myelin sheat of the neurons, acting as a decoy for attacking immune cells
- Mitoxantrone (Novantrone): Can be used in SPMS. It is an antineoplastic agent also used in cancer therapy - Natalizumab (Tysabri): “Anti-Integrin” mAb, used in MS and Crohn’s.
o MoA: Attempts to counteract the autoimmune aspect of the disease by preventing adhesion of lymphocytes to the vascular endothelium. IV drug given every 28 days
Fingolimod (Gl): The first MS Oral drug – it was a “phenotypic” drug discovery - Discovery: Natural product derived from fungi, ISP-I (Myriocin). It was noticed to
have immunosuppressant properties, inhibiting serine palmitoyltransferase, though it was toxic and poorly soluble greasy surfactant chain. Issues include:
o We do not like the double bond or ketone = Sites for metabolism o We don’t like the polar head group because of the stereocenters (complex) o It lacks a chromophore so we cannot monitor it
- ISP-I Optimization: It was a hit, but now we have to optimize it towards a lead o (1) Elimination of Chiral Centers (Chiral centers are hard to multiply and purify) o (2) Remove Side Chain Functionalities (Reactive, Unpredictable metabolism) o (3) Vary Chain Length (Just experimenting)
§ Immunosuppressant Model – Mean Survival Time (MST) Experiment in rat skin allografts. Discovered that 14-15 carbons are optimal for immunosuppressant properties.
§ Toxicity Experiments showed 15 carbons are more toxic than 14. o (4) Incorporation of Phenyl ring to improve ADMET and facilitate spectroscopic detection at low
concentrations o (5) Vary chain length again
- MoA: Prevents the release/egress of lymphocytes (and other inflammatory.mediators) from lymph nodes. Thus, these immune system components will not cross the vascular endothelium and cause damage. This mechanism does not include the serine palmitoyltransferase.
- Molecular MoA: o Bioactivation: Fingolimod requires bioactivation for activity. Phosphorylation of a
hydroxyl group establishes Fingolimod-Phosphate as a Sphingosine-1-Phosphate mimic. It therefore can be recognized by the sphingosine phosphate (SP) receptor.
§ SP Receptors are 7-transmembrane GPCR with an extra N-terminal loop. Sphingolamide-Phosphate, the natural endogenous agonist, causes functional antagonism through negative feedback. Receptor is internalized, slowing/inhibiting Leukocyte migration.
o Receptor Agonism: Fingolimod-Phosphate is an agonist at S1P1/3/4/5 but not S1P2. § S1P1: Fingolimod-Phosphate agonism of this receptor, similar to Shingolamide-Phosphate,
causes functional antagonism and internalization of the receptor. This inhibits leukocyte egress and protects the CNS from accumulation and further attack. Also minor cytoskeleton disruption.
• These receptors are located in the lymph nodes. § S1P3: Agonism at the Type 3 Receptor disrupts the cytoskeleton, inducing
cardiac side effects like Bradycardia. This is regarded as toxicity § S1P5: Agonism at the Type 5 Receptor elicits neuroprotective properties
- Fingolimod-mods: The next generation of optimized natural products. Cardiotoxicity in the form of prolonged QT, is suspected to be due in part by Fingolimod action at S1P3 receptors. Recent molecular adaptations have been made to alter affinity for these off-target sites at the 1,2 diol.
o Ozanimod (Celgene): S1PR1 > S1PR3 x10,000 – Showing improved cardiac safety o Ponesimod (Actelion): S1PR1 > S1PR3 x650 o Siponimod (trials): S1PR1 > S1PR3 x10,000
Teriflunomide: A oral disease modifying agents (DMARD) - MoA: Teriflunomide is essentially 3 molecules in 1, existing as tautomers through stereoisomeric relationships. It
inhibits dihydroorotate dehydrogenase, thus preventing de novo pyrimidine synthesis in T and B cells. As a result, Teriflunomide is antiproliferative and produces an anti-inflammatory effect.
o Teriflunomide is more effective against activated lymphocytes - Fun Fact: Teriflunomide is the active metabolite of leflunomide
(11/28) Federle Lecture: Medchem and Pharmacology of DMARDs in Rheumatology Perpetuation of an Autoimmune Disease: Rheumatic diseases like Rheumatic arthritis are often trapped in a damaging loop of autoimmune reactions. Initiated by an environmental component, such as injury or infection, stimulation of the immune system may propel an individual into this vicious cycle. There may be genetic factors at play, imparting a greater tendency leaning towards the pro-inflammatory side of things. Tissue damage will re-stimulate T cells, developing auto-aggressive T cells, and more cytokines
- The goal of treatment is to break this cycle. Targets of the Cycle: Mast cells release inflammatory mediators, in the form of:
- Membraned-Derived Lipid Mediators: Lipid metabolism, over the course of minutes, will release Prostaglandins, such as Leukotrienes, Platelet Activation Factor
o à Intervention: Cox Inhibitors - Cytokine Production: Over the course of hours, new mRNA and protein synthesis of: IL-1,3,4,5,6,8, TNF
o à Intervention: DMARDS, Synthetic (MTX, LFN, SSZ, HCQ) and Biological (mAb) - Re-tipping the Balance: Cytokines play a major role in RA, and adjusting pro/anti-inflammatory balance is the
