1st archetypal structure or
screen validating compound
2nd archetypal structure or
Desired Hit Profile
Desired Lead Profile
Please give 1-3 archetypal structures for the
most promising active chemical series being
exploited. Ideally the structures shown should
be that of the best example of an individual
series, and each series should differ in
chemical backbone rather than merely
substituents. You should indicate clearly where
this is not the case.
In subsequent sections please summarise the
available data requested in the same column to
allow the answers to be read as a table. Clearly
reference any values that you have included
from the literature if included instead of or as
well as your own data.
Indicate the description(s) that apply to the
compounds / series you have shown above.
Please delete the options that do not apply.
The intended route of administration has a
marked influence on the required properties
and characterisation of a small molecule. It may
also determine the appropriate expert reviewer
of your application. What is the proposed
clinical route of administration?
Please delete the options that do not apply.
Please indicate the level of characterisation and
quality control that has been performed on the
compounds described. Do the structures refer
to ‘solution actives’, compounds tested or retested from characterised solid, or compounds
resynthesised by the project, fully
characterised and re-tested? Indicate the
estimated chemical purity and technique(s)
used to determine this (500 words maximum).
Natural ligand / Research tool / Existing licensed drug / A drug-like compound reported in the patent
literature / A drug-like compound reported in peer-reviewed literature / Virtual screen output from a
pharmacophore/homology model based on X-ray/crystal structure / Proprietary drug-like hit/lead
Topical / Intravenous / Subcutaneous/parental / Inhaled / Oral / Other/unknown
For the exemplar structures given, please
specify the activity seen in i) the primary assay;
ii) in any secondary / cellular assay; and iii) in
any selectivity or promiscuity assay,
particularly cytotoxicity (500 words maximum).
For the series containing the given structure,
please specify the range of activity in i) the
primary assay; ii) a secondary / cellular assay;
and iii) any selectivity or promiscuity assay.
Please give the number of compounds tested in
each structural series and outline the main SAR
to date (500 words maximum).
Please indicate the following properties
(specific values and series ranges where
available): molecular weight; ligand efficiency
(LE), clogP, PSA; and any available
physicochemical / ADME data e.g. aqueous
solubility; microsomal stability data; plasma
protein binding; permeation measurements;
efflux measurements; CYP450 inhibition; hERG
binding (500 words maximum).
What is the evidence for these compounds
binding to the desired target?
Please outline the technique (X-ray
crystallography, NMR, DSC, SPR, covalent
linkage etc.) and the results. If direct evidence
is not available, what steps have been taken to
eliminate artefactual sources of assay activity,
i.e. promiscuity, aggregation, fluorescence,
protein reactivity, redox or other assay specific
processes? (500 words maximum)
Please indicate any measured in vivo ADME
parameters in a rodent species including (if
applicable): plasma clearance; %F
bioavailability; i.v. plasma half-life. (500 words
maximum)
Please indicate any measured ADME
parameters in a non-rodent species including
(if applicable):
plasma clearance; %F bioavailability; i.v.
plasma half-life. (500 words maximum)
Is there consistency in the in vitro metabolism
rates across non-clinical species and man?
Are in vitro metabolism profiles similar, if
known? (500 words maximum)
Has any assessment (computational or
experimental) of structural liability for reactive
metabolites, genotoxicity or phospholipidosis
been carried out? If so, please give details (500
words maximum).
Has any general broad target enzyme, ionchannel or receptor screening been carried
out? Please give details of any binding
observed (500 words maximum).
Please detail any overt physical signs observed
during in vivo studies performed to date (500
words maximum).
Highlight the key medicinal chemistry
challenges to optimisation of the chemical
series and the target profile that the project will
deliver during the scope of the award. What are
the desired characteristics of the Hit, Lead or
optimized Lead that the project seeks to
achieve? (500 words maximum)