Chemistry Reference
In-Depth Information
8
PRECLINICAL AND CLINICAL
STUDIES
Marcus E. Brewster,
1
Geert Verreck,
1
Jan Bevernage,
1
Joachim Brouwers,
2
Guy Van den Mooter,
2
and
Patrick Augustijns
2
1
Drug Evaluation
—
Pharmaceutical Sciences, Johnson & Johnson
Pharmaceutical Research and Development,
Janssen Pharmaceutica, Beerse, Belgium
2
Laboratory for Drug Delivery and Disposition,
KU Leuven, Leuven, Belgium
8.1 INTRODUCTION
Contemporary drug pipelines are increasingly populated with dif
cult-to-formulate drug
substances [1
uent
trends: (i) the reliance of the drug discovery process on high-throughput screening [4,5],
(ii) growing issues with drug form [6,7], and (iii) the nature of current drug targets that is
often associated with structure
-
3]. The genesis of this heightened complexity is rooted in three con
activity relationships (SAR) that deviate or disconnect
from the chemical space associated with good oral bioavailability and acceptable
biopharmaceutical
-
fitness [8,9]. High-throughput screening is thought to subselect for
compounds with high lipophilicities and low water solubilities, for compounds with
higher molecular weights and entopic
flexibility, and for related properties thought not to
be conducive for good absorption [4]. Drug form concerns are similarly related to the
