CPSA Digest 2002

Proceedings -Wednesday, October 9, 2002

WeOD3

Influencing Chemists to Minimize Attrition

Background
Drug metabolism groups are able to guide drug discovery research and minimize attrition by identifying the characteristics of drug-like compounds and screening for these aspects early in the development process. Some of the primary drivers for drug discovery
metabolism at Pfizer (Groton) are to:

• Guide Discovery Chemistry to identify and synthesize "drug-like" compounds
• Identify pharmacokinetic-related issues early in development and to positively influence Clinical plans
• Predict human pharmacokinetics and drug metabolism of new chemical entities

Attrition at Pfizer has been reduced by proper identification of pharmacokinetic-related issues early within the drug discovery phase of drug development.

Premise
At Pfizer, some of the primary reasons for attrition of drug candidates are safety, pharmacology and poor ADME characteristics.

The ratios are shown below:

In terms of poor ADME characteristics, clearance is the dominant cause of attrition; the ratios documented at Pfizer are: poor absorption-20%, poor clearance-64% and poor distribution-16%.

Historically (before 1995), attrition of new chemical entities due to pharmacokinetics was almost 20%. Recently, from 1997 to 2001, pharmacokinetic-related attrition was slightly over 10%. This decrease has been attributed to better screening and identification
of drug metabolism problems earlier in the discovery process. This effort is now making a real difference and in terms of support; resources were increased 50% to achieve this goal.

Analysis
The development of a D4 antagonist for schizophrenia was used as a representative example of this iterative process performed within drug metabolism discovery support. The project goal was to develop a compound with once-a-day or twice-a-day dosing. In order to accomplish this increased duration of effect in vivo, the strategy adopted was to decrease cytochrome P450-mediated drug metabolism in the liver.

The basis for the chemical structure of this D4 antagonist is shown below. The piperazine nitrogen (distal to the aniline nitrogen) was identified as key to D4 binding. Some of the chemical modifications made to this base structure were to add steric bulk at the alpha and beta carbons and to modify the benzimidazole (e.g., alter the electron withdrawing effects and add substituents to alter binding to CYP450). Metabolic information on half-life and clearance in the rat and human were compiled.

This iterative process continued and a propyl linker was tied into the ring. There were dozens of examples in the literature of compounds undergoing N-demethylation from an N-methyl-piperidine ring, but no examples of an N-decyclohexylation. Different series of substituents were synthesized and evaluated, including a spiro series, a bicyclooctyl series and an azabicyclic series. An important lesson learned from this work was that incorporation of
nitrogen into a ring structure resulted in a decreased rate of N-dealkylation.

Another example was shared of an unnamed and proprietary Pfizer development compound in which drug metabolism data were used in an iterative process to influence synthesis of improved analogues that did not ring-open, displayed low hepatic extraction ratios and maintained high pharmacological activities.

Value of the Technology
Prospective predictions of effective human half-lives over the years 1998-2000 revealed the following:

• Over 50% are cleared by non-CYP450 metabolism
• Discovery Chemistry was influenced to minimize P450-mediated metabolism, thus driving the clearance mechanism to non-CYP450 metabolism

An example of following this strategy has shown that no substrates have been nominated as development compounds since 1995 that displayed 100% CYP2D6-mediated metabolism.

References and/or Links
S. Venkatesh and R.A. Lipper, "Role of the Development Scientist in Compound Lead Selection and Optimization", Journal of Pharmaceutical Sciences, 89(2) (February 2000) 145-54.

"Drug Discovery: Filtering Out Failures Early in the Game", Chemical & Engineering News, 78(23) (June 5, 2000) 63.

S.J.F. Macdonald and P.W. Smith, "Lead Optimization in 12 Months? True Confessions of a Chemistry Team," Drug Discovery Today 6(18) (2001) 947-953.

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