Lead-like Drugs: A Perspective

Lead-like
drugs, or drugs below molecular weight 300, are an important
and sometimes overlooked component of the current pharmacopeia and
contemporary medicinal chemistry practice. To examine the recent state-of-the-art
in lead-like drug discovery, we surveyed recent drug approvals from
2011 to 2017 and top 200 prescribed medications, as well as provide
case studies on recently approved lead-like drugs. Many of these recent
drugs are close analogs of previously known drugs or natural substrates,
with a key focus of their medicinal chemistry optimization being the
choice of a low molecular weight starting point and maintaining low
molecular weight during the optimization. However, the identification
of low molecular weight starting points may be limited by the availability
of suitable low molecular weight screening sets. To increase the discovery
rate of lead-like drugs, we suggest an increased focus on inclusion
and prosecution of lead-like starting points in screening libraries.