James Empfield

Reducing the Risk of Drug Attrition Associated with Physicochemical Properties

Publisher Summary This chapter focuses on reducing the risk of drug attrition associated with physiochemical properties. 93—96% of nominated candidate drugs fail at some stage of development; all attrition, from the start of compound optimization in the discovery phase of a project to launch on the market, is probably closer to 99%. Therefore, there is an urgent imperative to directly address the reasons for attrition, which from candidate drug nomination onwards can be divided into three broad categories: Compound related, Biology related, and Organization related. Attrition is higher in the central nervous system (CNS) area compared to other therapy areas, partly because the need to cross the blood–brain barrier presents an additional challenge. Toxicity attrition occurs not only within clinical trials but continues post approval. During the past few years, a significant growth in the understanding of the links of the physical properties of drugs to drug attrition has occurred. A very considerable body of evidence suggests that drug metabolism and pharmacokinetics (DMPK) and toxicity outcomes are related to physical properties of compounds, which are under the control of medicinal chemists and other project scientists in drug discovery projects. Adopting a “zero-tolerance” attitude to compound-based failure in the clinic would lead to fewer candidate nominations, but also to increased clinical success.

Real-Time in Situ Raman Analysis of Microwave-Assisted Organic Reactions

Integration of a Raman probe into a commercially available microwave synthesizer has demonstrated unprecedented utility in understanding chemical processes within the rapidly emerging field of microwave-assisted organic synthesis. The real-time spectral feedback afforded by this system has facilitated analysis of reaction mechanisms, reactive intermediates, and reaction kinetics via optical sampling through the sidewall of the sealed reaction vial within the microwave chamber. The feasibility, attributes, and limitations of the system are illustrated using amine coupling and Knoevenagel coupling example reactions. In addition to the reported analyses, this system provided the safety of remote sensing, adequate sensitivity, ease of alignment, and optimized “depth of field” for analysis of solutions with solids content.

Experimental solubility profiling of marketed CNS drugs, exploring solubility limit of CNS discovery candidate.

We determined the experimental solubility of CNS marketed drugs. Of the 98 drugs measured, greater than 90% had solubility >10 μM in pH 7.4 buffer. Only seven drugs had solubility <10 μM. Using these data, we established a solubility criterion to support CNS discovery. The implication of poor solubility with potential safety concerns and undesirable side effects are discussed.

Synthesis of 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones as NMDA glycine-site antagonists

Several members of the 7-chloro-2,3-dihydro-2-[1-(pyridinyl)alkyl]-pyridazino[4,5-b]quinoline-1,4,10(5H)-triones (2) have been identified as being potent and selective NMDA glycine-site antagonists. Increasing size of the alkyl substituent on the alpha-carbon led to a progressive decrease in binding affinity. Some of these analogues possess improved drug-like properties such as cellular permeability, solubility and oral absorption.