The changing landscape of medicinal chemistry optimization

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Pharmaceutical Sciences

Background:

• Small-molecule drug discovery aims to develop chemical entities for clinical trials.
• This involves iterative optimization of molecular properties from hit to lead to drug candidate stages.
• Assessing property changes over time reveals trends in medicinal chemistry strategies.

Purpose of the Study:

• To analyze the impact of medicinal chemistry optimization on molecular properties of drug candidates.
• To compare drug candidates and their precursors from recent literature (2015-2022) with those from an earlier period (2000-2010).
• To examine internal drug discovery programs at AstraZeneca and Novartis for similar trends.

Main Methods:

• Comparative analysis of physicochemical properties of hit, lead, and drug candidate compounds.
• Literature review of drug candidates and their developmental stages between 2000-2010 and 2015-2022.
• Analysis of internal medicinal chemistry program data from AstraZeneca and Novartis.

Main Results:

• Observed shifts in key physicochemical properties of drug candidates over time.
• Identified strategic changes in medicinal chemistry programs influencing optimization pathways.
• Recent drug candidates exhibit different molecular property profiles compared to older ones.

Conclusions:

• Medicinal chemistry optimization strategies have evolved, impacting the properties of drug candidates.
• Understanding these trends is crucial for guiding future drug discovery efforts.
• The study highlights significant changes in the molecular characteristics of successful drug candidates over the past two decades.