Fueling the Pipeline via Innovations in Organic Synthesis

Abstract

The paramount importance of synthetic organic chemistry in the pharmaceutical industry arises from the necessity to physically prepare all designed molecules to obtain key data to feed the design–synthesis–data cycle, with the medicinal chemist at the center of this cycle. Synthesis specialists accelerate the cycle of medicinal chemistry innovation by rapidly identifying and executing impactful synthetic methods and strategies to accomplish project goals, addressing the synthetic accessibility bottleneck that often plagues discovery efforts. At AbbVie, Discovery Synthesis Groups (DSGs) such as Centralized Organic Synthesis (COS) have been deployed as embedded members of medicinal chemistry teams, filling the gap between discovery and process chemistry. COS chemists provide synthetic tools, scaffolds, and lead compounds to fuel the pipeline. Examples of project contributions from neuroscience, cystic fibrosis, and virology illustrate the impact of the DSG approach. In the first ten years of innovative science in pursuit of excellence in synthesis, several advanced drug candidates, including ABBV-2222 (galicaftor) for cystic fibrosis and foslevodopa/foscarbidopa for Parkinson’s disease, have emerged with key contributions from COS.

The Time and Place for Nature in Drug Discovery

“…This Perspective presents rationales and prospects for an increased focus on natural motifs and natural processes in drug discovery, bringing together concepts, observations, and opportunities to support and implement the hypothesis. Such methods are perhaps at odds with contemporary drug discovery practices, where practitioners remain heavily focused on a numbers-driven process through screening of molecules that can be made rapidly and cheaply, − contrasting to former practices of targeting designed natural product-like or biomimetic structures that often required more complex syntheses . The following discussion is not about natural products per se, a subject well-covered in recent reviews, − rather the contextualisation of the importance of the features and motifs inherent to physiological molecules and bioactive exogenous natural products is presented .…”

Synthesis of A-9758, an Inverse Agonist of Retinoic Acid-Related Orphan Receptor γt

“… This compound inhibits release of IL-17A both in vitro and in multiple animal models of inflammation. Due to increased compound demands that accompanied late-stage preclinical research activities, a new synthetic route was needed to accelerate access to decagram quantities of A-9758 ( 1 ) …”

“…Due to increased compound demands that accompanied late-stage preclinical research activities, a new synthetic route was needed to accelerate access to decagram quantities of A-9758 (1). 15 The original medicinal chemistry route to A-9758 involved 14 total synthetic steps (11 steps longest linear sequence). It was designed around a Larock indole synthesis strategy where 5 could be replaced with other o-iodoanilines for the diversification of indole substituents at carbons 4−7 (Scheme 1).…”

“…Due to increased compound demands that accompanied late-stage preclinical research activities, a new synthetic route was needed to accelerate access to decagram quantities of A-9758 ( 1 ). 15 …”

Advancing New Chemical Modalities into Clinical Studies

“…The rapid advancement of novel approaches in synthetic organic chemistry 9 has played a critical role in the development of efficient structure activity relationship (SAR) analysis and modular synthesis, identifying key precursors and quickly incorporating variation of the structure to improve selectivity or the PK profile. While it is possible to tune their physicochemical properties to enable suitable permeability and solubility, in general, they are stable enough to be compatible with most drug formulation approaches and routes of administration.…”