Optimization of Preclinical Metabolism for Somatostatin Receptor Subtype 5-Selective Antagonists

Abstract

A series of structurally diverse azaspirodecanone and spirooxazolidinone analogues were designed and synthesized as potent and selective somatostatin receptor subtype 5 (SSTR5) antagonists. Four optimized compounds each representing a subseries showed improvement in their metabolic stability and pharmacokinetic profiles compared to those of the original lead compound 1 while maintaining pharmacodynamic efficacy. The optimized cyclopropyl analogue 13 demonstrated efficacy in a mouse oral glucose tolerance test and an improved metabolic profile and pharmacokinetic properties in rhesus monkey studies. In this Communication, we discuss the relationship among structure, in vitro and in vivo activity, metabolic stability, and ultimately the potential of these compounds as therapeutic agents for the treatment of type 2 diabetes. Furthermore, we show how the use of focused libraries significantly expanded the structural class and provided new directions for structure−activity relationship optimization.

Into the Fray! A Beginner's Guide to Medicinal Chemistry

“…[151] suppressing oxidation by replacing or removing the alkoxy groups, replacing the biaryl system with electron-deficient heterocycles, as well as introducing additional electron-withdrawing halogens. [162] A subset of this library (110)(111)(112)(113)(114) maintained activity comparable to compound 109 with good activity against the human orthologue of SSTR5, but diminished activity against the mouse equivalent. Unsurprisingly, the lower activity against the mouse variant resulted in poorer in vivo activity in their mouse model.…”

“…These latter transformations in particular were identified as potential metabolic risk factors for compound development. [162] Working with a hypothesis that the dual resonance electrondonating ethoxy substitutions were activating the region toward metabolic oxidation, they applied a traditional medicinal chemistry workflow, investigating the electronic and positional effects of a variety of structural modifications, which would mitigate some of the metabolic lability, whilst maintaining desired biological activity. Here their primary strategy involved Figure 18.…”

“…Importantly, however, compound 114 in particular exhibited improved metabolic stability, with no oxidation products detected in their assay, thus providing an important insight into the structural requirement of this class, which balance target activity, and metabolic stability. [162]…”

Biocatalytic Construction of Spiro-Oxazolidinones via Halohydrin Dehalogenase-Catalyzed Ring Expansion of Spiro-Epoxides

“…Oxazolidinones are an important class of five-membered heterocyclic compounds with diverse applications in organic synthesis. − Additionally, they hold great importance in the field of medicinal chemistry because of their ability to exhibit a broad spectrum of biological activities. − An excellent example is the antibacterial agent linezolid, which is used to treat infections caused by susceptible Gram-positive bacteria. , In the past decades, spirocyclic scaffolds have gained significant attention and have found widespread applications in the fields of pharmaceutical and natural product. − In particular, spiro-oxazolidinones possess a distinct combination of spirocyclic and oxazolidinone motifs, which confer unique properties to these compounds and open up new avenues for drug design and development. As shown in Scheme , spiro-oxazolidinones have demonstrated a wide range of biological activities, including anticancer, anti-inflammatory, antiviral, antithrombosis, and antidiabetic complications. − Fenspiride, for example, possesses selective β2-adrenergic receptor agonist activity and is used to treat respiratory conditions …”