Complete Accounts of Integrated Drug Discovery and Development: Recent Examples from the Pharmaceutical Industry. Volume 4

This chapter highlights the discovery and chemical development of MK-1454, a cyclic dinucleotide STING agonist that has progressed to clinical trials as an immune stimulant for the treatment of solid tumors. The medicinal chemistry effort that culminated in the discovery of MK-1454 leveraged X-ray crystallography, modeling, and a variety of synthetic innovations including biocatalytic synthesis, to enable evaluation of a large number of cyclic dinucleotides for STING agonist activity. Additional innovation in P(III) chemistry enabled delivery of clinical supply, overcoming many challenges associated with the intrinsic complexity of this phosphorothioate cyclic dinucleotide drug candidate. Finally, a multi-step biocatalytic cascade enabled by directed evolution of an engineered animal cGAS (cyclic guanosine adenosine synthase) was developed, providing a diastereoselective, single pot synthesis of this complex structure in extremely high yield and efficiency.

Nucleoside analogues have emerged over the last decades as a well-established platform to treat cancer and viral infections. This chapter describes the discovery and chemical development of the nucleoside prodrug adafosbuvir (AL-335), a potent inhibitor of hepatitis C virus RNA-polymerase. The medicinal chemistry efforts resulted in the design of 4'-fluoro-2'-C-methyluridine with a proven mechanism of action toward HCV polymerase. Phosphoramidate prodrug strategy was applied leading to clinical candidate adafosbuvir and its efficacy and safety were demonstrated in vitro and in vivo. The route definition, the initial scale-up route, and the optimization towards large-scale production will be discussed.

We describe the discovery and development of a highly-potent, orally-bioavailable estrogen receptor full antagonist and degrader – giredestrant (GDC-9545) as a treatment for estrogen receptor-positive breast cancer. After a brief introduction on breast cancer and a rationale for targeting the estrogen receptor, an overview of the medicinal chemistry effort that led to the discovery of giredestrant and our initial medicinal chemistry route is presented. Subsequently, we provide details of how an efficient manufacturing route was developed to support mid- and late-stage clinical trials.

This chapter will describe the discovery and synthesis of the clinical compound BMS-986142, a selective, reversible, non-covalent inhibitor of Bruton’s tyrosine kinase. The compound benefits from chirality derived from a tertiary chiral center and two rotationally stable atropoisomeric axes, providing a single atropisomer out of eight possible diastereomers. An iterative medicinal chemistry effort to understand the impact of atropisomerism on potency, selectivity, and tolerability is highlighted. Additionally, the transition to process development and evolution of the route across stages of development leading to the proposed commercial synthesis with a focus on controlling the two chiral axes are reported.

Activation of the tumor suppressor p53 is widely regarded as a promising axis for treating a range of human cancers. AMG 232 is a small molecule designed to disrupt the protein-protein interaction between p53 and its negative regulator, MDM2, leading to increased tumor suppressive activity. The discovery of AMG 232 stems from a de novo design effort that was closely informed by protein co-crystal structures of known inhibitors at the time. From a micromolar starting point, an iterative, structure-based design process was used to optimize both anticipated and unexpected contacts between the inhibitors and the MDM2 protein by exploiting conformational control. The result was a compound possessing picomolar binding affinity for MDM2 within a unique and stereochemically rich chemotype. A robust process to prepare AMG 232 was developed. Highlights of those development efforts include the following: (i) use of a new bench-stable Vilsmeier reagent, methoxymethylene-N,N-dimethyliminium methylsulfate, for selective in situ activation of a primary alcohol intermediate; (ii) use of a novel stable isopropyl calcium sulfinate reagent ensuring reliable manufacture of a sulfone intermediate; (iii) development of a safe ozonolysis process performed in an aqueous solvent mixture in either batch or continuous manufacturing mode; and (iv) control of the drug substance purity by crystallization.

The discovery and chemical development of BMS-986251, a clinical RORγt inverse agonist, as a potential treatment option for autoimmune diseases is described. This chapter will outline the biology of the target (RORγt), the rationale for developing RORγt inverse agonists for the treatment of psoriasis and other autoimmune diseases, the discovery approach to identify and optimize the series for potency, efficacy and safety leading to BMS-986251, the medicinal chemistry approach to the synthesis of BMS-986251 followed by transition to process chemistry. In addition, the development and execution of an enabling route to support early toxicology and clinical studies, and the exploration and definition of an optimized route to enable long term development goals, will be detailed.

This chapter describes the research program that led to the discovery of amcenestrant, an oral selective estrogen receptor degrader for the treatment of patients with estrogen receptor positive breast cancer. We discuss the medicinal chemistry strategy that led to the selection of this clinical candidate. Additionally, we describe the optimized synthetic route that provided the final process for multikilogram preparations.

We outline the discovery and the process development for risdiplam, a potent oral splicing modifier approved as Evrysdi^® for the treatment of spinal muscular atrophy. The evolution of the manufacturing process is described from the discovery route to the commercial process for this highly accelerated project that was commercialized only 4.5 years after the start of clinical trials. We present the various synthetic approaches that have been pursued to support different stages of the preclinical and clinical development and discuss the issues that led to the development of the final commercial process.

The molecular complexity of small molecules entering clinical development has increased over the last decade. This, coupled with increasing demands for accelerated progression through the clinic, introduces challenges for process chemistry. New, stage appropriate, strategies and technologies are required to deliver safe, robust chemical processes that are cost effective and environmentally sustainable.