Medicinal chemistry rules of thumb: myths and realities in CNS drug discovery

(D. Martin Watterson, Northwestern University)

Definitions and concepts:

  • Pharmacokinetics (PK) – What the body does to a drug
  • Pharmacodynamics (PD) – What the drug does to the body
  • Adverse pharmacology and toxicity – Potential new drugs are subjected to rigorous preclinical animal studies in order to forecast the probability of adverse effects in humans. This is based on the concept that all drugs show adverse effects at some dose.
  • Therapeutic index – Difference between desired pharmacology outcomes over a dose range verses adverse pharmacology/toxicology observed with increasing dose; reflects interplay between PK and PD
  • Molecular properties of a drug – Physical characteristics that contribute to how a molecule will alter or be altered by complex biological systems

The general process of drug discovery: target ID and validation, lead discovery and optimization, preclinical development, clinical trials, regulatory approval.

Risk generally falls into 2 categories: adverse pharmacology/toxicology or efficacy. This can be related to drug candidate or the target itself.

The current approach is to push failure earlier in the timeline to minimize risk, using the following principles:

  • “Smart chemistry” : driven by the biological goal; based on achieving fewer, more drug-like molecules; chemotype diversity is expanded within molecular property limits
    • Integrate decision filters based on informatics (e.g. structure, chemistry, pharmacology) and feasibility screens (e.g. pharmacology, mechanism of action, therapeutic window, extended PD). Use early Go/No Go decision steps to minimize risk, save time and cost.
    • More is not better, either in chemical libraries or in synthetic efforts.
  • “Smart biology” : early screens to address risk, especially with major barriers in the particular disease area (e.g. CNS penetrance and distribution)

By using an iterative approach that integrates early medicinal chemistry refinement and pharmacology-related screens, fewer high-quality compounds are produced for early in-vivo feasibility tests (see FIG. 1).

There is a focus on small molecules because of an extensive knowledge base. A preponderance of currently approved drugs are small molecule-based.

  • In particular, natural products have been a historical source of drugs. However, natural products cannot be assumed to be inherently safer than synthetic products (e.g. arsenic).

“Off label” use of approved drugs is another method of obtaining new treatments for a disease. This is not necessarily a safer process; FDA-approved drugs being tested for another disease indication requires addressing safety pharmacology, formulation and dosing issues.

  • The risk for non-efficacy is increased if the drug does not have the appropriate properties for the new indication.

Small molecule rule of thumb: diversification of a starting point compound

  • Inexpensive raw materials can be readily modified using established synthetic schemes to produce related chemotypes.
  • Structure-activity landscapes can be steep (diversification alterations have large effects on pharmacology) or flat (little impact from structure changes).
  • If using a compound with a steep landscape, keep in mind that chemical diversification could generate major improvements OR loss of activity; additionally, metabolites might generate more active or toxic products.
    • Test early for metabolic stability potential, active metabolites and other ADMET properties.
  • If using a compound with a flat landscape, activity outcomes from chemical diversification can be more readily forecasted; however, major changes in activity/function may be difficult to evolve after a certain point.
    • Take more than one chemotype into the early discovery phase.

PK/PD interface is a critical planning issue, especially for disease modifying drugs.

  • If the underlying biological process is well-understood and well-targeted, the drug does not need to be continually present. Treatment should be aimed for the clinically relevant time window.

It is important to remember that hits are not drugs – plan on extensive medicinal chemistry refinement or reformulation.

Basics of high throughput screening (HTS): Bridging chemistry and biology >