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Fundamentals of Bio Orgo > Chemical Methods for Improving PK > Flashcards

Flashcards in Chemical Methods for Improving PK Deck (37):
1

the main parameters of optimizing pharmacokinetics are

aqueous solubility, chemical and metabolic stability, intestinal absorption

2

structural bioisoteric qualities

size shape hbonding

3

receptor interaction bioisoteric qualities

hbonding, electronic

4

log P < 5 makes for

increased oral bioavailibility

5

can you add or remove functional groups in the pharmacophore to improve hydrophylicity/hydrophobicity?

not so much, the pharmacophore is important!

6

T/F: Adding or removing functional groups is a practical method for improving hydrophobicity?

F

7

adding polar groups ______ the logP

decreases

8

modifying _______ is a way of altering hydrophobicity

potential ionization sites

9

pH of stomach

1-4

10

pH of small intestine

7-8

11

amide bonds are ____ to stomach pH

very susceptible

12

use of ____ can help prevent amide hydrolysis

amide bond mimics

13

name three ways to prevent degridation by peptidases and esterases

bond mimics, steric shields, bioisoteres

14

steric shields use ___ to ______

a large steric group/ block enzyme from degrading

15

problem of steric shields:

adding a large FG often changes PK properties

16

to prevent degredation, we use ___ to make compound more stable and resist cleavage

electron donating

17

_ in liver metabolizes many drugs

CYP450

18

General metabolism: ______ then _______

oxidation/ conjugation

19

CYP450 wants to make compounds ______

more water soluble

20

CYP450 metabolizes at two main sites for aromatics:

methyl groups, para position to R group

21

Solution to CYP450 metabolism:

use bioisoters

22

species difference in metabolism is a major consideration in preclinical testing of prodrugs

true

23

Type I prodrugs:

intracellular site of conversion

24

Type IA prodrugs:

converted in therapeutic target tissue

25

Type IB prodrugs:

converted in metabolic tissues

26

Type II prodrugs

extracellular site of conversion

27

Type IIA produrgs:

converted in GI fluid

28

Type IIB prodrugs:

converted in systemic circulation

29

metabolic tissues are:

liver and lungs

30

liberation of prodrug:

active drug molecule is intact within overall structure of the prodrug

31

bioactivation of prodrug:

must be converted into a new chemical structure - can be chemical or metabolic conversion

32

ester prodrugs are commonly used to

enhance membrane permeability of easily ionizable carboxylic acid

33

rate of cleavage is affected by ________ of ester

electronic effects

34

_____ speed up cleaveage of ester prodrugs by making the ester ___

electron withdrawing groups/ unstable

35

_____ speed down cleavage of ester prodrugs by making the ester ____

electron donating groups/ stable

36

antibody drug conjugates:

prodrugs tied to antibodies --> target only certain cells

37

trojan horse prodrugs:

allows a compound to get into cell and then convert to active form