Drug Discovery & Development PHC 311 LEC. 3 Sunday 9/ 11/ 1434H

2 Drug Optimization: Strategies in drug design I-optimizing drug target interactions Drug optimization aims to maximize the interactions of a drug with its target binding site in order to improve activity, selectivity and to minimize side effects. Designing a drug that can be synthesized efficiently and cheaply is another priority. The aim of drug optimization can be achieved by different strategies or approaches on the lead compound SAR, such as;

General approach 1- Molecular disjunction (molecular dissociation, dissection or simplification) 2- Molecular conjunctive approach a- Molecular addition b- Molecular replication c- Molecular hybridization

II. Special approach 1. Ring closure or ring opening 2. Ring expansion and ring contraction 3. Homologation and chain branching 4. Introduction of unsaturation center 5. Introduction, removal or replacement of bulky groups 6. Changes of substitution position 7. Introduction of chiral center 8. Conformation restriction (molecular rigidification) 9. Isosteres and bioisosteres

1. Ring closure or ring opening Diethylstilbesterol may be regarded as a ``ring opening`` modification of estradiol

Closure of a chain or opening of a ring

Ring chain transformation has important pharmacokinetic effect as it increase the lipophilicity and decrease the metabolism. So this makes the drug more active in vivo.

2. Ring expansion and ring contraction

3. Homologation A homologous series is a group of compounds that differ by a constant unit, generally a CH 2 group.

This phenomenon corresponds to Increased lipophilicity of the molecule to permit penetration into cell membranes until its lowered water solubility becomes problematic in its transport through aqueous media. In the case of aliphatic amines Micelle formation is a problem which begins at C12. This effectively removes the compound from potential interaction with the receptors. e.g. 1: Hypnotic activity of alcohols  The maximum effect occurred for 1-hexanol to 1-octanol.  The potency declined on chain lengthening until no activity was observed for hexadecanol. e.g. 2: 4-alkyl substituted resorcinol derivatives [Antibacterial effect is maximum in case of 4-n-hexyl resorcinol ]

Chain branching Chain branching decrease the potency. The branched side chain is less lipophilic than the straight one. The branched chain may interfere with: - ADME. - Receptor interaction.

Chain branching Chain branching lowers the potency of a compound because a branched alkyl chain is less lipophilic than the corresponding straight alkyl chain. in case of [Homologation] lipophilic relationship is important The lowered potency may be due to  pharmacokinetics (Absorption, metabolism, excretion,……..etc.)  pharmakodynamics Chain branching may interfere with receptor binding

e.g. 1: Phenyl ethyl amine It is an excellent substrate for monoamine oxidase (amphetamine) [It is a poor substrate for MAO] e.g. 2: Primaquine is more potent than its secondary or tertially amine analogues.

e.g. 3: 10-aminoalkylphenothiazines These examples indicate that multiple receptors are involved for 10-aminoalkyl phenothiazines. Branching or homologation can cause the molecule to bind more or less well to the receptors responsible for antispasmodic, antihistaminic, tranquilizing, or antipruritic activities.

4. Introduction of unsaturation center The introduction of an unsaturated group (vinyl, allyl, ethenyl, ethynyl……….etc) in a drug molecule alters its stereochemistry and physicochemical properties and consequently affects its biological activity.

The increase in hypnotic activity of ethylene (general anaesthetic) than the saturated derivative

5. Introduction, removal or replacement of bulky groups This special process is used mainly to: Convert agonist to antagonist or Prevent the enzymatic degradation

6. Changes of substitution position The position of certain groups is sometimes essential for given biological for a given biological. For example, the three isomers of hydroxybenzoic acid only the o-hydroxy is active, because it can form an intramolecular hydrogen bond and, in this way, it can act as a chelating agent.

7- Introduction of chiral centers Receptors are chiral entities and the interactions of many drugs at specific sites chirality of interaction. Introduction of chiral centers can alter drastically its pharmacological activity. e.g. the four isomers of choramphenicol, only the D-(-)- threo-form is active. L-(-)-ascorbic acid has antiscorbutic activity wherease (+) ascorbic does not. R(-)-isomer of epinephrine is more potent on both α- and β- adrenergic receptors than the S(-)-isomer.

8- Conformation restriction (molecular rigidification) The antimigrain, sumatriptan, undergoes rapid oxidative metabolism of the aminoethyl side chain to the inactive indolacetic acid. Conformmational restriction to give the cyclic piperidine analogue retains the antimigraine activity, but has much longer duration.

The simple addition of α-methyl group to give ACE inhibitor captopril increased by 10-folds over the des-methyl compound.

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)

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 times more potent than morphine - Low addictive potential - recently indicated as a therapeutic agent for the treatment of heroin addiction rigidity increases potency

Rigidification is used on flexible lead compounds. The aim is to reduce the number of conformations available while retaining the active conformation. Locking Rotatable rings into ring structure or introducing rigid functional groups are common methods of rigidification.

9. Isosteres and Bioisosteres

Why..?

Bioisosterism

Bioisosterism is a lead modification approach that has been shown to be useful to attenuate: Toxicity Modify the activity of a lead May have a significant role in the alteration of metabolism of the lead

Parameters affected with isosteric replacement Size Conformation Polarity H-Bond formation Solubility Hydrophobicity Reactivity

Classification of isosteres 1- Classical. 2- Non-classical.

Classical Bioisosteres 1.Monovalent atoms and groups (C, N, O, S) 2.Divalent atoms and groups (R-O-R, R-NH-R, ) 3.Trivalent atoms and groups (R-N=R, R-CH=R) 4.Tetrasubstituted atoms ( =C=, =N=, =P=,) 5.Ring equivalents Nonclassical Bioisosteres 1.Exchangeable groups 2.Rings versus noncyclic structures The nonclasical bioisosteres do not rigidly fit the steric and electronic rules of the classical bioisosteres

Thank you