Biomedical Engineering Reference
In-Depth Information
enzymatic cleavage, and generally limits them to indications compatible with par-
enteral administration.
Macrocycles occupy a unique position between these two chemical spaces in terms
of molecular properties [1a], with molecular weights ranging from 400 to 1500 Da.
At equivalent molecular weight, they generally possess fewer degrees of freedom and
are more conformationally restricted than their linear congeners, which represents
an advantage for oral absorption, other parameters aside [3,7]. This is controlled by
several factors, such as ring size, ring strain, the orientation of exocyclic substituents
and transannular interactions. In the context of a biological target, this translates into
a reduced entropic loss upon binding, provided that preorganization mimics a binding
conformation. Owing to their ability to display distant pharmacophores on conforma-
tionally restricted templates, macrocycles have the potential to recapitulate the large
interaction surfaces of biological molecules such as antibodies. This is demonstrated
convincingly by the isolation of the first antagonist of the IL-17 receptor, which exem-
plifies the ability of this class to mimic an antibody-protein interface [8]. Macrocycles
have successfully provided drug candidates for most biological target classes; how-
ever, their use in drug discovery is limited by the lack of broadly applicable synthetic
methods capable of generating the diversity required for lead optimization in medic-
inal chemistry [1a and c], despite great advances in the total synthesis of complex
macrocyclic natural products of various chemical classes [9]. Indeed, as opposed to
total synthesis, which favors convergent approaches, lead optimization requires the
generation of multiple analogs and several points of synthetic divergence, in order to
generate the necessary diversity that will deliver a development candidate endowed
with the optimal balance of properties. As it stands today, no fewer than 100 drugs
are macrocycles, most of which are peptidic or natural product derivatives [10]. The
predominance of these two categories largely reflects synthetic accessibility: natu-
ral products are available as such and can generally be biosynthesized or extracted
from natural sources, whereas peptides benefit from robust and automated production
methods [9e,10,11].
In summary, macrocycles have the potential to tackle targets that represent high-
hanging fruits in terms of druggability; however, they also constitute high-hanging
fruit in terms of synthetic challenge and diversity generation. Technologies for macro-
cycle synthesis and diversification have given rise to several platforms that constitute
the foundation of companies incorporated in the last decade [12].
In the following paragraphs, we first discuss some general issues inherent to
macrocycles and their synthesis, then we cover diversity generation strategies that
have either demonstrated their potential for drug discovery or that appear very promis-
ing among different chemical classes of macrocycles. The reader is referred to earlier
reviews for additional information and examples [1c,9c and d,10,13].
8.2 CHALLENGES ASSOCIATED WITH MACROCYCLES
8.2.1 Synthetic Challenge
Synthetically, the main hurdle in the path toward macrocycles is the need to overcome
entropy and favor an intramolecular reaction over the competing intermolecular
