drug discovery exam 3

library based drug discovery

screens many compounds against target to find hits

• includes combinatorial chemistry

• and parallel phase synthesis

what served as the start of library based discovery

automated peptide synthesis

what is automated peptide synthesis

uses a resin made out of polystyrene as a protecting group to act as a solid support

benefits of automated peptide synthesis

• compound wont be dissolved in multiple layers

• can use many reagents without worry of them washing away

• no cross couplings would contaminate products

• can sequentially perform multiple steps

split pool strategy

strategy of splitting up products and redistributing them

combinatorial chemistry

idea of making combinations of starting materials to generate a large number of products using solid phase synthesis.

problem with combinatorial chemistry

there is not a good method for separating the different products

RF tags

• separate specific compounds of out of pools of products

• By attaching RF tags to each resin bead and using a computer to track what compound is being built on each one, the instrument can read the tag and automatically determine which reaction flask that bead needs to go into for the next synthetic step

drawback to solid phase organic synthesis and why

• compounds are cleaved with Friflouroacetic acid which leads to decomposition of product

• inefficient removal of TFA leads to short shelf life

alternatives to solid phase organic synthesis

• flourous technology

• parallel organic synthesis

solution phase synthesis can mimic the benefits of using solid phase synthesis with

• teabags

• immobilized reagents

• immobilized scavengers

can you pool solution phase synthesis

no

compounds made with solution phase have a greater ___ and do not require a ___

shelf life; cleavage step

convergent synthesis

• converges multiple steps and cutes down on the number of steps

• plays a role in the solution phase synthesis of new analogs

parallel organic synthesis

introduces modifications as late in the synthesis as possible, started as a way to made amide bonds. in solution phase.

• can use automation

• reactions are done seperately

advantages to the availability of a high number of analogs

• removes synthesis as a bottleneck to progress

• more confidence

• access to SAR

reactions that introduce late stage diversity

• parallel organic synthesis

• suzuki synthesis

suzuki coupling reaction synthesis

• makes a carbon-carbon bond or a boronic acid (ester) without adding an H bond acceptor or donor and doesnt add to total PSA

buchwald hartwig reaction

• makes an aryl bromide (C-N or C-O)

• brings complex groups together

• needs palladium

suzuki and buchwal rxn are good

• work well on heterocycles

• tolerant of typically reactive functionality

• amendable to solid phase synthesis

• dont need protecting groups

• can be done on solid support

automation can speed up…

synthesis, purification, and analysis

lead optimization steps

1, confirm what is needed for activity

2. determine optimal distance between interacting groups-if flexible then make it rigid- avoid stereochemistry

3. knock out groups to see which is important

4. after optimal subst- reexamine prior optimizations

isostere

substances that are similar in properties because they have the same number of valence electrons in the same arrangement- not because they have the same number of atoms

biosisostere

substituents with similar properties that produce similar biological properties in a chemical compound

bioisostere example

• replacing a hydrogen with a flouride or a CH3 with a CF3

• amide bioisosteres

• tetrazole replaces COOH

• tetrazole replaces carboxylate

why is flouride replacing H good

• C-F bond is not broken by CYPs- not metabolized

• blocks oxidation of methyl group

• downsides are greater MW, more lipophilic, inc logP

heterocycles

• serve as bioisosteres of aromatic rings

• can be proton donors or acceptors

• mimic many functional groups

benzene can be replaced by

5 ring with sulfur

can replace peptide bonds with

heterocycles

PROTAC/TPD

• you can mark proteins with ubiquitin to inhibit it since its being marked for degradation to target protein-protein intxns

prodrugs

when the active substance is not the drug

animal models

• xenografts (animal to person)

• immunodeficient mice to study tumors

• biomarkers are responses measured from living organism

ways to measure efficacy (does it do what we want)

• rat paw edema test

• rat flick test

• mental state (forced swim test)

• disease progression

• progression free survival

• waterfall plot (tumor growth)

how to know if statistically significant

if two standard deviations above

biologics

substance derived from animal products for treating/preventing disease

• not orally bioavailable

ab suffix

biologic/antibody

umab

humaized antibody

imab

from primate

biologics can be generated using

recombinant DNA tech for antibodies

why can biologics not work

bc proteins undergo post translational modification or folding

biologics pros

• hyperspecific

• low toxicity/adverse effects

biologics cons

• poor PK-IV only

• expensive

IND

investigational new drug application- filed to get permission from the FDA to start human trials. where drug generic and normal name is decided and approved.

IND requires

• protocols used to analyze compound

• plans and protocols to be used during trials

• details about drug candidate

• details about how and where compound will be prepared and purity

• details about pharmacology and toxicology

companies must follow guidelines for

GLP- laboratory

GMP- manufacturing

GCP- clinical

physiochemical details required

• structure

• MW

• MP

• pka, logP, logD

• optica rotation

• proof of structure

• form

• stability

salt selection study

• counterion of drug plays large role in PK

• form of drug studied via X ray powder diffusion (XRPD or XRD)

• allows for identification of diff polymorphs- ability of solid material to exit in more than one form

drug must be tested against (physical)

• light

• heat

• mechanical

• hygroscopidity

• florida test- drug sits in oven for 24 hrs

CMC group

chemical manufacturing and control- optimizes synthesis of drug on large scale

good to avoid what in large scale synthesis

• reactions w low temps

• slow controlled additions

• chromatographic purifications

cGMP facilities have (certified GMP)

• record of thorough documentation and compliance

• all reaction components are of documented quality

• components can be reliably supplied

how to limit costs

do only the last step in a cGMP facility by making other intermediates available from other sources. Give up some IP, but saves money.

what detail needs to be provided for each reactant

• source

• purity

• grade

methods of detecting impurities

• triple qudrapole mass spec

• NMR w other nuclei

• elemental anlysos

• chemical derivization

FDA purity

every impurity that exists above 0.05% or one that they would be exposed to above 1.0mg/day must be accounted and tested for

what is used to study toxicology

• MBI (mechanism based inhibition) of CYPs

• hERG

• maximally tolerated dose (>100g)

• Ames test for mutagenicity

Ames test

if drug reverses bacterias mutation that allows growth in histidine deficient medium, then flagged as a potential mutagen

IB

investigators brochure- info provided to the clinicians who will be studying the compound. includes pertinent safety data and drug characterization

Phase 1

• first in humans

• PK profile- multiple dose

• single clinic

• determines safety and MTD (max tolerated dose)

• adverse events (1-5) are graded

• IND specifies what would be considered MTD

• at singular site

• determine SAE (seriou adverse effects)

phase 2

• examines effiacy

• multiple GCP facilities

• many IND apps are written as a combo of phase I and II

• participants are aware of the study and role

• if very good- will be approved

IND of combo phase I and II risks and why it is necessary

• necessary to find number of people to participate in risky study (cancer)

• complicated bc studying efficacy before safety

• can cloud SAE cause

phase 2 parts

IIA- dose range finding

IIB- can statistical efficacy be seen

RDT

new type of phase 2 trial- randomized discontinuation trial that tries to overcome phenonomen of positive thinking in trials. Patients who show efficacy are switched from test to control group.

patients per phase

I- tens

II- hundreds

III- thousands

phases 2 and 3 are ___ studies

efficacy

phase 3

• new IND

• comparison to standard of care

• multiple GCP facilities

• test and control group

• double blind

• 22% improvement must be met

• unblinded when certain conditions are met

DSMB

data an safety monitering board

• established for each trial

• reviews data and evaluates safety and efficacy

• reports findings after data is unblinded

• can stop trial for a group or the whole thing

tuskegee trial

study that enrolled african american men eith syphilis but never told them even if they infected others. Study lasted 40 years. led to various changes in clinical trials

changes made after the tuskegee study

• informed consent of all participants

• accurate communication of any diagnoses

• DSMB establishment

• establishment of IRB for all clinical trials

clinical trials cost

$150k/patient for each trial

50 for phase 1

500 for phase 2

5,000 for phase 3

why is it impossible to complete clinical trials for cancer and alzheimers

the length of time

average time to go from IND application to completion of phase 3 trial

8 years

success rates for clinical trials

phase 1- 63%

phase 2- 31%

phase 3- 58%

adds up to 10% success rate

NDA

new drug application, used when phase 3 trial is complete. contains all data to make case on why drug should be approved. more than 10k pages

SPA

special protocol assessment. Establishes what would be considered statistical significance before the trial begins. If fda agrees then drug is automatically approved after completion of the NDA.

FDA advisory commitee

meetings are public, they advise the FDA on what they should do.

if approved, FDA makes restrictions about…

• labeling and claims (black box label)

• off label use

what do most phase 3 trials do

they are for drugs that have already been approved in other therapeutic area

can a drug be prescribed for any use

yes, but might not be covered by insurance

emergency use authorization

drug can be approved without FDA approval beforehand in emergencies. Was used for covid and before that for diagnostic tests.

PDUFA

prescription drug user fee act to get expedited review. 4 million dollar fee charge for fda to consider new drugs for approval

phase 4 trials

• for drug/drug interactions

• translational medicine (other effects it might have)

how long to go from concept to clinic approval

10 years

hatch-waxman act

• alt name: drug price competition and patent term restoration act

• did two things

  • any new molecular entity is given 5 years of exclusivity

  • established ANDA- a bioequivilant drug should be approved as a generic component

  • incentivizes people to break patents

what does bioequivilance mean

same bioactive component is in the same concentration as the approved drug.

• only needs phase 1 trial

• least expensive

• no PDUFA fee

ANDA

abbreviated new drug application (for generic drugs)

hatch waxman act incentives for generic drugs

• gov cover legal costs of patent challenges for first group to file ANDA

  • 180 dat exclusivity for first successful ANDA

how do generic drugs come to be

use a route not protected by a patent- changes not considered obvious

6 reqs for patentability

• usefulness

• novelty

• nonobviousness

• written desc

• enablement

• best mode

greatest challenge to patents

best mode for synthesis

how do large countries have low per capita sales

do not respect intellectual property, and companies that fight it end up with many charges

advantage of biologics over molecules

immune to generics

disadvantages for discovering a drug for an orphan disease

• helps few amt of people

• limited opportunity to recover costs

• limited patient pop for clinical trials

orphan disease

• disease that affects less than 200,000 people in the US

OOPD

office of orphan products development-governs orphan designations

orphan drug act and benefits

• incentivized companies to find drugs for orphan diseases

• tax credit equal to 50% of clinical testing costs

• access to federal assistance to pay for clinical testing (loss of confidentiality)

• 7 years of exclusive rights to market drug for orphan indication

• regulatory guidance for clinical trials (removes possibility of failure)

what drugs have mainly been approved for orphan diseases

those that target diseases with veryyy low infectious rates

how has the ODA been exploited

companies had failed drugs- folded- were sold to big pharma that used the tax credits for profit

running out of antibiotic agents

• new antibiotics will be held out

• incentive is hospital subscription to medicines

CDER

center for drug evaluation and research

• evaluates prescription drugs and other claims