A co-processed active pharmaceutical ingredient (CP API) is the combination of an active pharmaceutical ingredient (API) with non-active component(s). This technology has been demonstrated to offer numerous benefits, including but not limited to improved API properties and stability. The infrastructure requirements are such that the manufacture of a CP API is typically best suited for an API facility. CP API has been regulated as either an API or as a drug product intermediate (DPI). This variability in the designation has led to ambiguities on the regulatory CMC expectations in the CP API including the stability of CP API and CP API containing products which, in turn has hampered the broader application of this technology in the pharmaceutical industry. This difference in designation also resulted in challenges to the lifecycle management of the regulatory documentation for the CMC information of the CP API. This white paper represents the proposals for the regulatory requirements on stability studies related to CP API and to drug product containing CP API by the CP API Working Group (WG) of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ). Additionally, considerations and the WG’s recommendations on the stability studies of CP API from different manufacturing sites or processes and post-approval changes for product containing CP API are described.

Pharmaceutical products represent a meaningful target for sustainability improvement and emissions reduction. It is proposed here that rethinking the standard, and often linear, approach to the synthesis of Active Pharmaceutical Ingredients (API) and subsequent formulation and drug product processing will deliver transformational sustainability opportunities. The greatest potential arguably involves API that have challenging physico-chemical properties. These can require the addition of excipients that can significantly exceed the weight of the API in the final dosage unit, require multiple manufacturing steps to achieve materials amenable to delivering final dosage units, and need highly protective packaging for final product stability.Co-processed API are defined as materials generated via addition of non-covalently bonded, non-active components during drug substance manufacturing steps, differing from salts, solvates and co-crystals. They are an impactful example of provocative re-thinking of historical regulatory and quality precedents, blurring drug substance and drug product operations, with sustainability opportunities. Successful examples utilizing co-processed API can modify properties with use of less excipient, while simultaneously reducing processing requirements by delivering material amenable to continuous manufacturing. There are also opportunities for co-processed API to reduce the need for highly protective packaging. This commentary will detail the array of sustainability impacts that can be delivered, inclusive of business, regulatory, and quality considerations, with discussion on potential routes to more comprehensively commercialize co-processed API technologies.

Abstract Elevated adenosine levels present in the tumor microenvironment (TME) produce a net immunosuppressive effect through inhibition of T cell function by two mechanisms of action: Direct T cell effects via A2A receptor agonism and indirect T cell effects via agonism of A2A and A2B receptors on myeloid cells. Our team sought to identify a small molecule dual antagonist of the A2A and A2B receptors with the ability to decrease the immunosuppressive effects of adenosine in the TME and restore anti-tumor immune response. Drawing on our prior experience in the design of A2A receptor antagonists for the potential treatment of Parkinson’s disease, we developed a molecule with sub-nanomolar and single-digit nanomolar affinities for the A2A and A2B receptors respectively and greater than 100-fold selectivity over the related A1 and A3 receptors. A single dose assessment of this molecule in human subjects demonstrated the ability to achieve >99% target engagement (TE) at the A2A receptor and >90% TE at the A2B receptor at trough concentration. This presentation will, for the first time, describe the discovery and early clinical evaluation of this molecule, including disclosure of the structure, human pharmacokinetics, safety, and tolerability. Citation Format: Duane DeMong, Sheila Ranganath, Jared Cumming, Matthew Larsen, Yonglian Zhang, Christopher Plummer, Amjad Ali, Anthony Palmieri, Evan Barry, Pierre Daublain, Pranav Gupta, Manash Chatterjee, Vincent Giranda, Jeremy Presland, Sebastian Schneider, Paul Ciaccio, Daniel Tatosian, Aaron Sather, Ben Turnbull, Steven Silverman, Harry Chobanian, Harini Krishnamurthy, Richard Wnek, Roshi Afshar, Stephen Crowley, Alita Miller, Mark Ayers, Alan Whitehead, Marlene Hinton, Derek Chiang, Robert Orr, Jill Chrencik. Discovery and clinical evaluation of a potent and selective A2A/2B dual receptor antagonist [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr PR017.

The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to distinguish among free amino moieties of insulin (two at amino termini and an internal lysine) and manipulate cleavable phenylacetamide groups in a programmable manner to form protected insulin derivatives. This enables selective and specific chemical ligation to synthesize homogeneous bioconjugates, improving yield and purity compared to the existing methods, and generally opens avenues in the functionalization of native proteins to access biological probes or drugs.

GPR40 (FFAR1 or FFA1) is a G protein-coupled receptor, primarily expressed in pancreatic islet β-cells and intestinal enteroendocrine cells. When activated by fatty acids, GPR40 elicits increased insulin secretion from islet β-cells only in the presence of elevated glucose levels. Towards this end, studies were undertaken towards discovering a novel GPR40 Agonist whose mode of action is via Positive Allosteric Modulation of the GPR40 receptor (AgoPAM). Efforts were made to identify a suitable GPR40 AgoPAM tool molecule to investigate mechanism of action and de-risk liver toxicity of GPR40 AgoPAMs due to reactive acyl-glucuronide (AG) metabolites.

A series of biaryl chromans exhibiting potent and selective agonism for the GPR40 receptor with positive allosteric modulation of endogenous ligands (AgoPAM) were discovered as potential therapeutics for the treatment of type II diabetes. Optimization of physicochemical properties through modification of the pendant aryl rings resulted in the identification of compound AP5, which possesses an improved metabolic profile while demonstrating sustained glucose lowering.

The evolution of synthetic chemistry approaches towards a green and sustainable synthesis of a HCV NS5b cyclic prodrug nucleoside (CPN) is described.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

Jamie M. McCabe Dunn,* Mikhail Reibarkh,* Edward C. Sherer, Robert K. Orr, Rebecca T. Ruck, Bryon Simmons and Ana Bellomo The direct and chemoselective 30-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 30-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 30-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach.

GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs. Compound 24 demonstrated sustained glucose lowering in a chronic study of Goto Kakizaki rats, showing no signs of tachyphylaxis for this mechanism.

The synthesis of the γ-secretase modulator MK-8428 (1) is described. The synthesis is highlighted by an enzyme-catalyzed reaction to access 3,4,5-trifluoro-(S)-phenylglycine, a 1-pot activation/displacement/deprotection sequence to introduce the aminooxy functionality and a dehydrative intramolecular cyclization under mild conditions to form the oxadiazine heterocycle of 1. In situ reaction monitoring was employed to understand the deleterious role of water during the formation of a methanesulfonate ester in the 1-pot activation/displacement/deprotection sequence.

A modular, selective approach to complex α-tertiary substituted malononitriles is reported. The method takes advantage of β-ester-substituted α,α-dinitrile alkenes as highly reactive, chemoselective electrophiles for 1,4-additions with organometallic nucleophiles to produce functionally and sterically dense all-carbon quaternary centers. In the presence of a chiral ester auxiliary bearing an aromatic ring, the 1,4-addition occurs with good to excellent selectivity due to favorable cation−π interactions. The highly functionalized malononitriles represent versatile building blocks and can be applied toward efficient, highly selective syntheses of 5,5-disubstituted pyrrolopyrimidinones.

Chiral chroman derivatives are important pharmacophores in natural and synthetic bioactive molecules. The discovery of catalytic asymmetric methods for the synthesis of these compounds is an important goal. Ruthenium-catalyzed asymmetric transfer hydrogenation under strongly basic conditions has been found to induce dynamic kinetic resolution of beta-substituted chromanones, producing valuable chromanols in high yields and with high levels of stereocontrol. The reaction proceeds by base-catalyzed racemization of the beta-stereocenter through a conjugate elimination/conjugate addition pathway in concert with a highly selective ketone transfer hydrogenation step. Computational analysis of the catalyst, substrate, and transition state structures has revealed the driving interactions for diastereoselectivity as well as unexpected CH-O stabilizing interactions between the catalyst sulfonamide and the reacting substrate.

The evolution of a scalable process for the preparation of methylcyclobutanol-pyridyl ether 1 is described. Key aspects of this development including careful control of the stereochemistry, elimination of chromatography, and application to kilogram-scale synthesis are addressed.

The paper describes the SAR/SPR studies that led to the discovery of phenoxy cyclopropyl phenyl acetamide derivatives as potent and selective GPR119 agonists. Based on a cis cyclopropane scaffold discovered previously, phenyl acetamides such as compound 17 were found to have excellent GPR119 potency and improved physicochemical properties. Pharmacokinetic data of compound 17 in rat, dog and rhesus will be described. Compound 17 was suitable for QD dosing based on its predicted human half-life, and its projected human dose was much lower than that of the recently reported structurally-related benzyloxy compound 2. Compound 17 was selected as a tool compound candidate for NHP (Non-Human Primate) efficacy studies.

Jamie M. McCabe Dunn,* Mikhail Reibarkh,* Edward C. Sherer, Robert K. Orr, Rebecca T. Ruck, Bryon Simmons and Ana Bellomo The direct and chemoselective 30-phosphoramidation, phosphorylation and acylation of nucleosides are described. Upon the discovery of a novel 30-phosphorylamidation of therapeutic nucleoside analogues with DBU, we explored the mechanism of this rare selectivity through a combination of NMR spectroscopy and computational studies. The NMR and computational findings allowed us to develop a predictive computational model that accurately assesses the potential for 30-functionalization for a broad range of nucleosides and nucleoside mimetics. The synthetic utility of this model was exemplified by demonstration on a broad scope of nucleosides and electrophiles yielding targets that were previously only accessible via a protection/deprotection sequence or an enzymatic approach.

The direct and chemoselective 3′-phosphoramidation, phosphorylation and acylation of nucleosides are described.