REVIEW
◥ORGANIC CHEMISTRY
The importance of synthetic chemistry
in the pharmaceutical industry
Kevin R. Campos^1 , Paul J. Coleman^1 , Juan C. Alvarez^1 , Spencer D. Dreher^1 ,
Robert M. Garbaccio^1 , Nicholas K. Terrett^1 , Richard D. Tillyer^2 ,
Matthew D. Truppo^2 , Emma R. Parmee^1
Innovations in synthetic chemistry have enabled the discovery of many breakthrough
therapies that have improved human health over the past century. In the face of increasing
challenges in the pharmaceutical sector, continued innovation in chemistry is required to
drive the discovery of the next wave of medicines. Novel synthetic methods not only unlock
access to previously unattainable chemical matter, but also inspire new concepts as to how
we design and build chemical matter. We identify some of the most important recent
advances in synthetic chemistry as well as opportunities at the interface with partner
disciplines that are poised to transform the practice of drug discovery and development.
O
ver the past century, innovations in syn-
thetic chemistry have greatly enabled the
discovery and development of important
life-changing medicines, improving the
health of patients worldwide. In recent
years, many pharmaceutical companies have
chosen to reduce their R&D investment in chem-
istry, viewing synthetic chemistry more as a ma-
ture technology and less as a driver of innovation
in drug discovery ( 1 – 3 ). Contrary to this opinion,
we believe that excellence and innovation in syn-
thetic chemistry continues to be critical to success
in all phases of drug discovery and development.
Moreover, recent developments in new synthetic
methods, biocatalysis, chemoinformatics, and re-
action miniaturization have the power to accel-
erate the pace and improve the quality of products
in pharmaceutical research. The application of
new synthetic methods is rapidly expanding the
realm of accessible chemical matter for modulat-
ing a broader array of biological targets, and there
is a growing recognition that innovations in syn-
thetic chemistry are changing the practice of drug
discovery ( 4 , 5 ). Here, we identify some of the
most enabling recent advances in synthetic chem-
istry as well as opportunities that we believe are
poised to transform the practice of drug discov-
ery and development in the coming years.
The pharmaceutical sector is currently facing
multiple challenges: an increasing focus on com-
plex diseases with unknown causal biology, a
rapidly changing and highly competitive land-
scape, and substantial pricing pressures from
patients and payers. In this challenging envi-
ronment, drug discovery scientists must select
biological targets of relevance to human disease
andfindsafeandeffectivetherapeuticmolecules
that appropriately modulate those targets. The
current toolbox of synthetic methods and com-
mon chemical starting materials provides ac-
cess to chemical space ( 6 ) that can be efficiently
explored and mined to identify a suitable ligand
and subsequently pursue studies of that prelim-
inary lead compound toward its potential devel-
opment as a successful drug. Brown and Boström
have noted that a historical overreliance on just
a few robust synthetic transformations (amide
bond formation, sp^2 -sp^2 C-C cross-coupling, and
SNAr reactions) has biased the output of many
drug discovery efforts, leading to narrow sampling
of chemical space ( 7 ). In other cases, the lack of
any reasonable method of synthesis has, at mini-
mum, hampered thorough evaluation of chem-
ical space or, at worst, prevented it completely.
Conversely, the discovery of breakthrough syn-
thetic methods can truly transform the processof drug discovery. Innovation in synthetic chem-
istry provides opportunity to gain more rapid
access to biologically active, complex molecular
structures in a cost-effective manner that can
change the practice of medicine. An outstanding
example of the transformative power of synthetic
chemistry in drug discovery is the application of
carbenoid N-H insertion chemistry to the syn-
thesis ofb-lactam antibiotics ( 8 ). In the 1950s,
the synthesis of antibiotics such as penicillin
represented a formidable challenge to medicinal
chemists, and broad exploration of structure-
activity relationships (SAR) within this class of
compounds was hindered by a lack of good meth-
ods of synthesis for these chemically sensitive
structures. Indeed, the first chemical synthesis of
penicillin took nearly a decade of dedicated ef-
fort to achieve ( 9 ) despite an intensive effort across
multiple laboratories. This lack of synthetic ac-
cessibility prevented thorough evaluation of struc-
turally related antibiotics that might have a
broader spectrum of activity and an improved
resistance profile. The application of intramo-
lecular N-H carbenoid insertion chemistry (Fig. 1)
to these structures provided a disruptive solution
to the preparation of these fusedb-lactams. This
synthetic method was applied to the preparation
of numerous natural and synthetic anti-infectives,
including thienamycin ( 10 ), which subsequent-
ly led to the discovery and industrial manufac-
ture of the antibiotic imipenem. In this example,
synthesis enabled design, opening access to pre-
viously unattainable molecules of high therapeu-
tic value.
The development of targeted medicines for
the treatment of chronic hepatitis C infection, a
global health challenge ( 11 ), illustrates another
key advance that innovative synthetic chemistry
has contributed to drug discovery in recent years.
The design and synthesis of hepatitis C virus
(HCV) NS3/4a protease inhibitors represents a
formidable challenge for medicinal chemists be-
cause the active site of this protease has a shallow,
open binding site, and the enzyme possesses both
genotypic and mutational diversity. Early studiesRESEARCH
Camposet al.,Science 363 , eaat0805 (2019) 18 January 2019 1of8
(^1) Global Chemistry, Merck & Co. Inc., Kenilworth, NJ 07033,
USA.^2 Janssen Research & Development LLC, Spring House,
PA 19477, USA.
*Corresponding author. Email: [email protected] (K.R.C.);
[email protected] (P.J.C.)
Fig. 1. Synthetic method innovations enable discovery of important anti-infectives, imipenem
and vaniprevir.
on January 19, 2019^
http://science.sciencemag.org/
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