Medchem Material Covered After Exam 2

what is a lead compound?

the first molecule with the desired pharmacological activity

where do lead compounds come from?

1. natural sources

2. serendipity: accidental discovery

3. screening

4. biochemistry

5. side effects from other drug classes

6. rational drug design

7. genomics/proteomics

ethnopharmacology

scientific study of ethnic groups, their physical habits, and how they use medicinal plants

what are the different types of compound libraries?

1. random

2. directed

3. in silico

what is the goal of lead modification?

increase potency and specificity

what is a pharmacophore?

3D arrangement of atoms that is responsible for the drug's activity

What is a metabophore?

3D arrangement of atoms that is responsible for the metabolic properties

What is a toxicophore?

3D arrangement of atoms that is responsible for toxicity-eliciting interactions

what is simplification of the complex?

sometimes parts of a drug can be removed and the drug will still be active

what is homologation?

A series of compounds where each member differs from the next by the presence or absence of a single methylene group (-CH2-).... insetring -CH2- groups between two parts of a drug molecule

free rotation around a single bond often produces...?

different conformations

introduction of rings restricts the shape of a molecule, making it more _________

rigid

breaking rings or removing them will allow a molecule to be ________

more flexible (may produce more side effects)

What are bioisosteres?

1. molecular shapes + volumes

2. similar distribution of electrons

what are examples of bioisosteres?

H and F

CH3, CF3 and Cl

CH3, NH2, and OH

Br and i-propyl [CH(CH3)2]

I and t-butyl [C(CH3)3]

methylenes can be replaced by... (and vice versa)

ethers, thioethers, selenoethers

amines can be replaced by... (and vice versa)

alcohols and thiols

ketones can be replaced by... (and vice versa)

esters, thioesters, amide, sulfoxide, sulfone, sulfonamide, nitrile

carboxylic acids can be replaced by.... (and vice versa)

sulfonamide, sulfonoic acid, phosphonate, tetrazole

T/F The more flexible a molecule is, the less specific it is.

true

the major excretory organ is...

kidney

what types of drugs are excreted often without needing major metabolism?

polar and ionized

a hERG pharmacophore:

- lipophilic base

- usually 3° amine

X = 2-5 atom chain, may include rings, heteroatoms, or polar groups

Which of the following groups would you add to a drug if you wanted to increase its dissolution.

carboxylic acid

What organ metabolizes drugs?

liver

which types of drugs are largely reabsorbed back into systemic circulation during passage through renal tubules?

lipophilic drugs

what is the goal of biotransformation?

To make drugs more water soluble so that they can be more easily excreted from the body.

what is Phase I metabolism?

polar functional groups are: introduced into the molecule OR modified by reactions: oxidation, reduction, hydrolysis

what is Phase II metabolism (conjugation)?

attaching small, polar, + ionizable endogenous molecules (i.e. glucuronic acid, sulfate, glycine, glutamine, and glutathione) to Phase I metabolite or parent drug

these molecules are often attached to polar groups introduced or unmasked in Phase I rxns (i.e. hydroxyls, carboxylates, amino groups

oxidation reactions include:

1. gain of oxygen

2. loss of a hydrogen

3. loss of an alkyl group

4. loss of a heteroatom

Where are cytochrome P450 enzymes found?

endoplasmic reticulum

these enzymes are membrane bound

isozymes

multiple forms of same enzyme

what are most of the drug metabolizing enzymes?

CYP 1, 2, and 3 families

oxidation of aromatic rings

- benzene gets an epoxide (arene oxide)

- arene rearranges to give para hydroxylated product

- ends with R group and an -OH para (arenol)

- EWG deactivate the ring (rxn wont proceed)

- EDG activate the ring

oxidation of alkenes

- non-aromatic dbl bonds

- epoxide intermediate

- can be opened up to form a diol (one bold, one dashed)

- only occurs if there is an H on each side of the alkene

Oxidation at allylic carbons

carbons directly adjacent to non-aromatic dbl bonds

oxidation only occurs if there is a hydrogen atom on the allylic carbon atom

oxidation of benzylic carbons

are aliphatic carbons directly attached to an aromatic ring

oxidation does not usually occur if there is a heteroatom attached to the benzylic carbon as well

oxidation of aliphatic and alicyclic carbons

aliphatic chains will go through oxidation at the second to last carbon

alicyclic rings undergo oxidation at the C3 or C4 position

oxidative deamination

losing amine... adjacent carbon must contain an H

oxidative d=N-dealkylation

2° or 3° amine... N still attached to drug

N-oxidation

N turns into N=O