Structural Approach to Assessing the Innovativeness of New Drugs Finds Accelerating Rate of Innovation

Abstract

Measuring innovation in the pharmaceutical industry is challenging. Counts of new molecular entities (NMEs) approved by the Food and Drug Administration (FDA) are commonly used, but this measure only gauges quantity not innovativeness. A new indicator of innovation for small molecule and peptide drugs based on structural novelty is proposed and used to analyze recent trends in pharmaceutical innovation. We show pharmaceutical innovation has significantly increased over the last several decades despite recent concerns over an innovation crisis and find Pioneers (a NME whose shape and scaffold were not used in any previously FDA-approved drugs) are significantly more likely to be the source of promising new therapies. Analysis of the underlying source of structural innovation indicates that scaffolds first reported in the CAS REGISTRY five or less years prior to their Investigational New Drug application (IND) or on scaffolds populated with 50 or less other compounds at the time of IND tend to be the main source of Pioneers. Our analysis also shows a widening structural innovation gap between large pharmaceutical companies (Big Pharma) and the rest of the ecosystem even though the number of Big Pharma originated Pioneers has increased.

Target-Based Evaluation of “Drug-Like” Properties and Ligand Efficiencies

“…It has become clear that applying “drug-like” properties in a generic manner can be questioned for three main reasons. First and most obviously, physicochemical descriptors themselves are surrogates for compound quality and are no substitute for robust experimental data. , Second, the physical properties of drugs, as well as discovery compounds, , vary according to their biological target (as well as target accessibility in vivo), observations that are important for the future as the number of new targets pursued in drug discovery efforts is significantly expanding. , Third, some of these physicochemical descriptors, notably MW, structural complexity, and polar surface area (PSA), are increasing significantly over time in marketed drugs, − and in discovery and patented compounds, − going into chemical space beyond the boundaries of the Ro5 (termed bRo5). − Collectively, these observations question the existence of a fixed “drug-like” physicochemical space.…”

Annulative Dimerization of Carbohydrates: Synthesis of Complex C2‐Symmetrical 1,4‐Dioxane‐Sugar Hybrids

“…With the optimized conditions in hand, we next explored the substrate scope of this unusual annulation reaction. A small range of known 1,6-anhydrosugarsderived hydroxyepoxides 9-12 [16,18] were evaluated (entries [14][15][16][17]. Unfortunately, only compound 13 was formed in 59 % yield starting from substrate 9 (entry 14).…”

“…Herein we described not only the selective preparation of chiral dioxanes from dimerization of 1,6‐anhydrosugars, but also its extension to the synthesis of other chiral dioxane‐carbohydrate hybrid compounds (Figure 1c ) . The introduction of carbohydrate functional groups around a dioxane framework is unexplored and could lead to complex organic molecules with potential interesting biological activities [15] …”

Tackling the reproducibility problem to empower translation of preclinical academic drug discovery: is there an answer?

“…and sector shortcomings that can contribute to failure of discovery campaigns [12,13,14,15,19,57]. Likewise, although senior principal investigators bear primary responsibility to ensure that students who wish to engage in careers as discovery practitioners The term "reproducibility" is used broadly herein to denote the ability of practiced researchers to verify the results of and draw the same overall conclusions from a published study independently of the original experimenters by using the methodological, experimental, and data analysis conditions specified in-print.…”

“…This infodemic of irreproducible published data has been estimated to encompass 50% of all published preclinical life-science research and waste around $28 billion annually in the United States alone [11]. entities (NECs) is more diversified than ever [12,13]. Yet steady increases in both research and development (R&D) costs for bringing novel medicines to market and discovery-project cycle times attend falling returns on R&D investment, unacceptably high rates of candidate failure in clinical trials, and erosion of public trust in the pharmaceutical industry [14,15,16].…”