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MICROBIOLOGY | Indicative Values | Project Data | |
MIC vs wild-type species | µg/mL | ≤ 16 | |
PHARMACOLOGY | |||
Target biochemical assay (IC50) | µM | ≤ 10 | |
SELECTIVITY | |||
Cytotoxicity vs mammalian cell line | TI | ≥ 10 | |
CHEMICAL DEVELOPMENT | |||
Tractable synthesis | – | Yes | |
Freedom-to-operate | – | Yes | |
Evidence of preliminary structure-activity relationships | – | Yes | |
Table 2. Additional criteria for a ‘Lead’ stage small-molecule asset
MICROBIOLOGY | Indicative Values | Project Data | |
MIC vs indication-relevant species (wild-type) MIC vs drug-resistant strain(s) | µg/mL µg/mL | ≤ 1 ≤ 4 | |
Frequency-of-resistance (4 Ч MIC) | – | ≤ 10-8 | |
Mode-of-action (time-kill method) | – | Bactericidal | |
Efficacy in ≥ 1 relevant models-of-infection | Δ log CFU | ≥ 3.0 | |
PHARMACOLOGY | |||
Target biochemical assay (IC50) | µM | ≤ 1 | |
Mechanism-of-action | – | Confirmed | |
SELECTIVITY | |||
Cytotoxicity vs mammalian cell line | TI | ≥ 50 | |
hERG inhibition (IC50) | µM | > 30 | |
PHARMACOKINETICS | |||
Plasma stability | % | > 90 | |
Microsome stability (EH ratio) | – | < 0.3 | |
Hepatocyte stability (EH ratio) | – | < 0.3 | |
Plasma protein binding | FU | > 0.1 | |
CYP450 inhibition (IC50) | µM | > 30 | |
Caco-2 permeability (PappA-B) Caco-2 efflux ratio | Ч 10-6 cm/s – | ≥ 1.0 ≤ 3.0 | |
Oral bioavailability (for PO route) | % | ≥ 20 | |
PHYSICOCHEMICAL PROPERTIES | |||
Solubility | µM | > 50 | |
Aqueous stability (pH 1-8) | % | > 90 | |
Molecular weight | Daltons | < 500 | |
LogP | – | < 5 | |
Lipophilicity | LogD7.4 | -1 to 4 | |
pKa | – | 3-9 | |
Polar surface area | Е2 | < 120 | |
CHEMICAL DEVELOPMENT | |||
Provisional patent (composition-of-matter, use) | – | Filed | |
Table 3. Additional criteria for a ‘Candidate’ stage small-molecule asset
MICROBIOLOGY | Indicative Values | Project Data | |
MIC90 (≥ 100 contemporary clinical isolates) | µg/mL | ≤ 4 | |
Frequency-of-resistance (4 Ч MIC) | – | ≤ 10-9 | |
Efficacy in ≥ 2 relevant models-of-infection | Δ log CFU | ≥ 3.0 | |
PK-PD parameter(s) | – | Defined | |
PHARMACOLOGY | |||
Target biochemical assay (IC50) | µM | ≤ 0.1 | |
SELECTIVITY | |||
Cytotoxicity vs mammalian cell line | TI | ≥ 100 | |
hERG Inhibition (IC50) | µM | > 100 | |
Off-target, e. g. CEREP, screen | – | No signals | |
PHARMACOKINETICS | |||
CYP450 Induction (IC50) | µM | > 10 | |
SGF/SIF stability | % | > 90 | |
CYP450 reaction profiling (3A4) | % | ≤ 75 | |
Metabolite profiling (for active, reactive metabolites) | – | None | |
Rodent PK | – | Acceptable | |
Non-rodent PK (e. g. dog) | – | Acceptable | |
SAFETY | |||
Genotoxicity (Ames and/or clastogenicity) | – | Negative | |
14-day general toxicology (rodent) | TI | >100 | |
CHEMICAL DEVELOPMENT | |||
International patent (composition-of-matter, use) | – | Filed | |
Table 4. Additional criteria for a ‘Clinical Candidate’ stage small-molecule asset
CHEMISTRY, MANUFACTURING AND CONTROLS | Indicative Values | Project Data | |
Analytical method validation | – | Yes | |
API manufacture at kg scale [GMP] | – | Yes | |
API stability testing [GMP] | – | Stable | |
PHARMACOKINETICS | |||
Rodent PK [GLP] | – | Acceptable | |
Dog PK [GLP] | – | Acceptable | |
NON-CLINICAL SAFETY PHARMACOLOGY | |||
In vitro genotoxicity [GLP] | – | Acceptable | |
In vivo genotoxicity [GLP] | – | Acceptable | |
In vitro hERG [GLP] | – | Acceptable | |
Dog CV study [GLP] | – | Acceptable | |
Rodent respiratory study [GLP] | – | Acceptable | |
Rodent CNS study, e. g. Irwin test [GLP] | – | Acceptable | |
TOXICOLOGY | |||
Rodent DRF study [GLP] | – | Acceptable | |
28-day rodent toxicology study [GLP] | – | Acceptable | |
Dog MTD study [GLP] | – | Acceptable | |
28-day dog toxicology study [GLP] | – | Acceptable | |
CLINICAL DEVELOPMENT | |||
Phase 1 development plan | – | Yes | |
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