Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?

An analysis of chemical reactions used in current medicinal chemistry (2014), three decades ago (1984), and in natural product total synthesis has been conducted. The analysis revealed that of the current most frequently used synthetic reactions, none were discovered within the past 20 years and only two in the 1980s and 1990s (Suzuki–Miyaura and Buchwald–Hartwig). This suggests an inherent high bar of impact for new synthetic reactions in drug discovery. The most frequently used reactions were amide bond formation, Suzuki–Miyaura coupling, and S_NAr reactions, most likely due to commercial availability of reagents, high chemoselectivity, and a pressure on delivery. We show that these practices result in overpopulation of certain types of molecular shapes to the exclusion of others using simple PMI plots. We hope that these results will help catalyze improvements in integration of new synthetic methodologies as well as new library design

Understanding Our Love Affair with <i>p</i>‑Chlorophenyl: Present Day Implications from Historical Biases of Reagent Selection

We report here an unexpectedly strong preference toward para substitution in phenyl rings within drug discovery programs. A population analysis of aromatic rings in various drug databases demonstrated that para substitution is favored over meta and ortho regioisomers, with <i>p</i>-chlorophenyl (<i>p</i>-ClPh) being one of the most predominant examples. We speculate that the frequency of <i>p</i>-ClPh is traced back to historical models of medicinal chemistry where para-substituted regioisomers were perhaps more easily accessed, and further reinforced by Topliss in 1972 that if Ph was active, the <i>p</i>-ClPh should be made because of ease of synthesis and hydrophobicity driven potency effects. On the basis of our analysis, the para bias has become useful conventional wisdom but perhaps so much so that a perception has been created that druglike space favors a linear aromatic structure. It is hoped this analysis will catalyze a new look at design of reagent databases and screening collections

Discovery and Preclinical Validation of [¹¹C]AZ13153556, a Novel Probe for the Histamine Type 3 Receptor

The histamine type 3 receptor (H₃) is a G protein-coupled receptor implicated in several disorders of the central nervous system. Herein, we describe the radiolabeling and preclinical evaluation of a candidate radioligand for the H₃ receptor, 4-(1<i>S</i>,2<i>S</i>)-2-(4-cyclobutylpiperazine-1-carbonyl)­cyclopropyl]-<i>N</i>-methyl-benzamide (<b>5</b>), and its comparison with one of the frontrunner radioligands for H₃ imaging, namely, GSK189254 (<b>1</b>). Compounds <b>1</b> and <b>5</b> were radiolabeled with tritium and carbon-11 for in vitro and in vivo imaging experiments. The in vitro binding of [³H]<b>1</b> and [³H]<b>5</b> was examined by (i) saturation binding to rat and nonhuman primate brain tissue homogenate and (ii) in vitro autoradiography on tissue sections from rat, guinea pig, and human brain. The in vivo binding of [¹¹C]<b>1</b> and [¹¹C]<b>5</b> was examined by PET imaging in mice and nonhuman primates. <i>B</i>_max values obtained from Scatchard analysis of [³H]<b>1</b> and [³H]<b>5</b> binding were in good agreement. Autoradiography with [³H]<b>5</b> on rat, guinea pig, and human brain slices showed specific binding in regions known to be enhanced in H₃ receptors, a high degree of colocalization with [³H]<b>1</b>, and virtually negligible nonspecific binding in tissue. PET measurements in mice and nonhuman primates demonstrated that [¹¹C]<b>5</b> binds specifically and reversibly to H₃ receptors in vivo with low nonspecific binding in brain tissue. Whereas [¹¹C]<b>1</b> showed similar binding characteristics in vivo, the binding kinetics appeared faster for [¹¹C]<b>5</b> than for [¹¹C]<b>1</b>. Conclusions: [¹¹C]<b>5</b> has suitable properties for quantification of H₃ receptors in nonhuman primate brain and has the potential to offer improved binding kinetics in man compared to [¹¹C]<b>1</b>

Azepines and Piperidines with Dual Norepinephrine Dopamine Uptake Inhibition and Antidepressant Activity

Herein, we describe the discovery of inhibitors of norepinephrine (NET) and dopamine (DAT) transporters with reduced activity relative to serotonin transporters (SERT). Two compounds, <b>8b</b> and <b>21a</b>, along with nomifensine were tested in a rodent receptor occupancy study and demonstrated dose-dependent displacement of radiolabeled NET and DAT ligands. These compounds were efficacious in a rat forced swim assay (model of depression) and also had activity in rat spontaneous locomotion assay