Graham F. Smith

Designing Drugs to Avoid Toxicity

Publisher Summary A quality development candidate compound after a positive proof of concept clinical trial has a good chance of making it to be a marketed drug. It is the role of medicinal chemists to choose the right compounds to design and synthesize. Although toxicity is now the joint primary cause of failure of clinical candidates, there is a growing body of information about structure–toxicity relationships even as those relate to complex bioactivation pathways. With this ever-growing knowledge, it should be possible for talented medicinal chemists to design inherently safer molecules. The introduction of a broader array of in vitro toxicology studies earlier in the drug discovery process should result in high quality development candidates entering the clinic and a richer database from which future structure–toxicity relationships may be discovered. As part of medicinal chemistry design, the properties of the molecules are predicted and decisions are taken based on those predictions. From measured physical and in vitro properties, it is also possible to predict pharmacokinetic and pharmacodynamic data to estimate the dose of development compounds. Good medicinal chemistry design, taking into account both potency at the target and also the predictive toxicology discussed in this chapter, increases the probability of a projects success and heavily influences speed of reaching a clear proof of concept outcome.

Medicinal Chemistry by the Numbers: The Physicochemistry, Thermodynamics and Kinetics of Modern Drug Design

Publisher Summary This chapter discusses key aspects of modern physicochemistry, thermodynamics, and kinetics that lead to good drug design. The classical view of medicinal chemistry is to work with the lock and key approach. The small molecule key is designed to fit the lock that is the target enzyme or receptor. The chapter explains the concept of binding energy, enthalpy, entropy, thermodynamic signatures, and ligand efficiency. Binding kinetics is also referred to as slow offset, slow off-rate, slow dissociation, insurmountable antagonism, ultimate physiological inhibition, tight binding and non-equilibrium blockade. The binding kinetics is described based on the theory of slow offset, kinetic maps, and various case studies. The chapter accounts for improved pharmacodynamics and the application of binding kinetics to kinases. Physical chemistry, in the form of the balance of binding energy contributions and target on- and off-rates, also plays a key part in delivering a good drug from a lead series. The physicochemistry of molecules can often indicate which molecules not to make, but is less prescriptive of what should be synthesised. Additionally, sometimes the numbers just do not add up and the various parameters required to deliver the drug concept are not available within the chemotype under evaluation or perhaps not even in the vastness of chemical space.

Discovery of 5-Amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide Inhibitors of IRAK4.

Interleukin-1 receptor associated kinase 4 (IRAK4) is an essential signal transducer downstream of the IL-1R and TLR superfamily, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides was developed via sequential modifications to the 5-position of the pyrazolopyrimidine ring and the 3-position of the pyrazole ring. Replacement of substituents responsible for poor permeability and improvement of physical properties guided by cLogD led to the identification of IRAK4 inhibitors with excellent potency, kinase selectivity, and pharmacokinetic properties suitable for oral dosing.

Identification of N-(1H-pyrazol-4-yl)carboxamide inhibitors of interleukin-1 receptor associated kinase 4: Bicyclic core modifications

IRAK4 plays a critical role in the IL-1R and TLR signalling, and selective inhibition of the kinase activity of the protein represents an attractive target for the treatment of inflammatory diseases. A series of permeable N-(1H-pyrazol-4-yl)carboxamides was developed by introducing lipophilic bicyclic cores in place of the polar pyrazolopyrimidine core of 5-amino-N-(1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamides. Replacement of the pyrazolo[1,5-a]pyrimidine core with the pyrrolo[2,1-f][1,2,4]triazine, the pyrrolo[1,2-b]pyridazine, and thieno[2,3-b]pyrazine cores guided by cLogD led to the identification of highly permeable IRAK4 inhibitors with excellent potency and kinase selectivity.

Discovery of selective RNA-binding small molecules by affinity-selection mass spectrometry.

Recent advances in understanding the relevance of noncoding RNA (ncRNA) to disease have increased interest in drugging ncRNA with small molecules. The recent discovery of ribocil, a structurally distinct synthetic mimic of the natural ligand of the flavin mononucleotide (FMN) riboswitch, has revealed the potential chemical diversity of small molecules that target ncRNA. Affinity-selection mass spectrometry (AS-MS) is theoretically applicable to high-throughput screening (HTS) of small molecules binding to ncRNA. Here, we report the first application of the Automated Ligand Detection System (ALIS), an indirect AS-MS technique, for the selective detection of small molecule-ncRNA interactions, high-throughput screening against large unbiased small-molecule libraries, and identification and characterization of novel compounds (structurally distinct from both FMN and ribocil) that target the FMN riboswitch. Crystal structures reveal that different compounds induce various conformations of the FMN riboswitch, leading to different activity profiles. Our findings validate the ALIS platform for HTS screening for RNA-binding small molecules and further demonstrate that ncRNA can be broadly targeted by chemically diverse yet selective small molecules as therapeutics.