Lead Modification

1. Lead Modification Objectives: Once a lead compound has been identified it must be altered to obtain the desired properties (maximize the therapeutic index and minimize side effects).   Alternatively, a known agonist can be structurally modified to make an antagonist or an inhibitor by maintaining the structural characteristics associated with binding and specificity but not "activation" of the biological activity. At the end of this lecture the student will know the concepts pharmacophore, based on the opioids, and the traditional methods used for optimization of lead compounds to improve their biological activity.

2. Identification of Pharmacophore Pharmacophore :Functional groups on a molecule that interact with the receptor and are responsible for binding and biological activity Modifications to lead compound • remove structural feature • add structural feature • block structural feature Functional groups most easily modified: • Hydroxyl (-OH) • Amino (-NH2, -NHR,-NR2) • Aromatic Rings • Double Bonds.

3. Hydroxyl Group Potential H-Bond Interations (H-donor or H-acceptor) Modifications to destroy these interactions: • Alkylation • Acylation • Reduction

4. Amino Group Potential H-Bond (H-acceptor) Possible Ionic interactions NH2 can be modified by: • Acylation • Alkylation

5. Aromatic Rings Involved in van der Waals interactions with “flat” hydrophobic regions in binding site. Double Bonds Similar to aromatic rings

6. Improvement of the “Lead” Compound • The lead may not be and “ideal” drug. • Structure Modifications increase potency • decrease side effects increase Therapeutic Index • alter route of administration • What can we do as Chemists? • change substituents • extend structure • chain extension/contraction • ring extension/contraction • ring variations • Isosteres • simplify structure • rigidification of structure • Variation of Substituents to optimize activity • Make changes to alter chemical or physical features • Basicity • Lipophilicity • electronic distribution • size steric bulk

7. Alkyl Substitutions • easily attached to alcohol, amine, phenol • vary chain length (bulk) • change basicity of amine • change lipophilicity • change selectivity

8. Alkyl Substitutions

9. Aromatic Substitutions • change substituents on ring • change substituent pattern

10. Extension of Structure • Add extra binding groups to search for nearby binding sites. As a result, • we may increase the binding affinity of the drug with binding site • By increasing the interactions of the drug with binding site, we could • prevent the natural substrate from binding (antagonist)

11. Chain Extension/Contraction Changes in the chain length between two binding groups may increase the interaction (and activity) of the drug with the binding site.

12. Ring Expansion/ Contraction Similar to previous chain modifications.

13. Ring Variations • Change aromatic or heteroaromatic to: • other heteroaromatic rings • different size rings • alter heteroatom positions Ring Fusions May change selectivity or increase interactions

14. Isosteres or Bioisosteres • A bioisostere is a chemical group which can replace another chemical group • without affecting biological activity (Functional groups with similar properties • {structural or chemical, such as hydrogen bonding ability}) • Classical isosters: Atoms (or groups of atoms) that have the same number of • outer shell e- . ■Often used to modify lead compound activity in order to: -minimize toxicity -alter metabolism -maximize bioavailability

15. Nonclassical Bioisosteres • Not included with classical isosteres • Will contain at least one similar • physical property, although structures • can differ significantly • Properties considered in bioisosteres • size • shape • hydrophobicity, pKa • chemical reactivity • hydrogen bonding capacity

16. Nonclassical Bioisosteres

17. Drug Daily Dosage Chlorpromazine (antipsychotic) 300-800 mg Chlorprothixene (antipsychotic) 50-400 mg Imipramine (antidepressant) 50-200 mg Maprotiline (antidepressant) 75-150 mg NOTE: Another example of ISOSTERIC replacement. The portion of the molecule modified is not directly involved in the interaction with the receptor but helps position other active elements of the molecule.

18. Simplification of Structure (molecular pruning) • Discard non-essential parts of drug structure • Benefit is a simple structure that is easier to synthesize.

19. Rigidification of Structure • may increase activity or decrease side effects. • multiple conformations allow interactions with more than one receptor (especially • true for neurotransmitters) • restriction of rotations allow only conformations necessary for binding at receptor • of interest and not receptors causing side effects. • One receptor may cause the desired effect while interaction with the other may • lead to undesired effects.

20. Improvement of Existing Drugs • Each lab wants it’s own antiulcer, antihypertensive, etc. Drug • Drugs are often “copied” by other companies to yield “me-too” products. • Generally, the company that owns the “original” drug will continue to prepare • new analogs to ensure maximum protection of patents. • Therefore, chemical modifications of known active molecules is one of the most • widespread practices in pharmaceutical research.

21. Improvement of Existing Drugs • Advantages: • Certainty of success. • Familiarity with pharmacological models to identify and quantify activity • Financial profitability. no investment in “fundamental” research required • Disadvantages: • May end up with a drug with an IDENTICAL ACTIVITY profile; selecting for same • activities, therefore, no real improvements • More difficult to achieve high sales because “copies” hit the market later than the • “original” and may be in competition with other “copies” • Justification = promise of improving existing drugs. The structures surrounding the • ß-lactam ring of PENICILLINS, for example, are still being modified. The results • have provided more selective and active against resistant strains and can be • administered orally. • Serendipity Factor • Pharmacological studies on the “copies” may show totally new properties! Thus • the “copy” becomes the new lead. • For example, Imipramine was synthesized as an analog of chlorpromazine and • examined for it’s antipsychotic activity. During the evaluation, it showed • more activity against depression than psychoses. As a result, it opened the • therapeutic doors for the treatment of depression.

22. Oral contraceptives are an example of physiological ligand modifications -Biochemical pathway: regulation of menstration and pregnancy -steriods (e.g. progesterone) identified as mediating compounds; therefore used as lead compounds -modification of physiological steroids leads to active agents (contraceptives)

23. Opioids as an example of a functional group modification to identify a pharmacophore

24. Remove tetrahydrofuran ring and hydroxyl at R' i) levorphanol ii) 3-4 times more potent as an analgesic than morphine iii) maintains addictive properties iv) therefore, tetrahydofuran ring and R' hydroxyl not essential for activity

25. Removal of half of the cylcohexene ring i) benzomorphan: partial separation of analgesic and addictive properties ii) cyclazocine and pentazocine: much lower addictive properties iii) therefore, cyclohexene ring contributes to the addictive properties

26. Removal of all fused rings i) Demerol: 10-12% potency of morphine ii) therefore, final fused ring not essential for analgesic activity

27. Acyclic analog Analgesic activity is still retained in many acyclic analogs due to the ability of those compounds to assume a conformation similar to that of the cyclohexane ring. i) Darvon: 1/2 to 2/3 as potent as codeine ii) Methadone: as potent an analgesic as morphine: less, but, still addictive iii) therefore, conformation of the substituents, not the rings themselves are important for activity

28. Structure of opioid pharmacophore Based on these studies the pharmacophore of the opioids is shown below Note that the six-membered ring that contains the nitrogen is not explicitly required for activity, just the conformational properties (space filling) associated with that type of functional group are required.

29. Increase rigidity and/or structural complexity Etorphine -two-carbon bridge -substituent not in morphine -1000x more potent than morphine - used in veterinary medicine to tranquilize large animals Buprenorphine -10 - 20 times more potent than morphine - Low addictive potential - recently indicated as a therapeutic agent for the treatment of heroin addiction rigidity increases potency

30. Functional group modification Chlorothiazide antihypertensize strong diuretic Diazoxide antihypertensize no diuretic activity

31. Homologation • Series of compounds that differ by a constant unit; generally a CH2 group – • (CH2)n- where n is varied. • Typically, an increase followed by a decrease in potency; note that the number of • CH2 groups associated with the maximum potency differs for the series of • compounds under study. • Changes in activity often associated with solubility/absorption issues. This will be • discussed in more detail later in the quantitative structure activity relationship • (QSAR) section of the course. • Micelle formation of amphiphilic (lipid-like) compounds, therefore, not available • to bind at receptor. This occurs when nonpolar tails are long and polar head • groups are present.

32. Homologation Relationship of potency to the number of methylene group

33. Chain branching • Chain branching of aliphatic chains • Tends to make compounds more lipophilic • Increased size of R-group could effect receptor binding • Phenethylamine: good monoamine oxidase (MAO) substrate (therefore readily • degraded) versus α-methylphenethylamine (amphetamine), which is a poor • substrate • Upon going from phenethylamine to amphetamine both the bioavailability and • activity is altered.

34. Primary through quarternary amines • Primary amines (Phenethylamine and amphetamine) are often more active • than secondary amines.

35. Chain branching (continued) 10-aminoalkylphenothiazine 1) -CH2CH(CH3)N(CH3)2 (promethazine) 2) -CH2CH2N(CH3)2 (diethazine)      for 1 and 2: antispasmodic and antihistaminic 3) -CH2CH2CH2N(CH3)2 (promazine)      decreased antispasmodic and antihistaminic activities      has sedative and tranquilizing activities 4) -CH2CH(CH3)CH2N(CH3)2 (trimeprazine)      reduced tranquilizing activity      antipruritic (anti-itch) activity

36. Ring-Chain Transformations Change alkyl substituent into cyclic analogs (or vice versa) Promazines: the following 2 drugs, chloropromazine and an analog, are equivalent as animal tranquilizers

37. Ring-Chain Transformations The following two drugs, trimeprazine and methdilazine, are equivalent as antipruritic agents in humans ring to chain transformations can be considered isosteric replacements