Diversity-Oriented Synthesis of Bioactive Azaspirocycles

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

“…Importantly, 66 shows highly selective binding to σ 1 over σ 2 receptors ( K i σ 2 = 696 nM) and several crucial CNS targets including 5-HT 2B ( K i = 231 nM), 5-HT 7 ( K i = 2765 nM), α 2A ( K i = 3364 nM), D 4 ( K i = 1283 nM), DAT ( K i = 2562 nM), H 2 ( K i = 823 nM), and KOR ( K i = 1707 nM) . In addition, Lepovitz and Martin synthesized bioactive azaspirocycles via a novel, efficient diversity-oriented synthesis (DOS) strategy that featured a tandem sequence involving imine formation and an aza-Sakurai reaction to form the spirocyclic system, and subsequently intramolecular Pictet–Spengler cyclization with formaldehyde to build tetrahydroisoquinoline rings. Azaspirocycle 67 shows a preference for the σ 1 receptor ( K i = 8 nM) with moderate binding at σ 2 ( K i = 152 nM) and α 2A ( K i = 531 nM) receptor and weak affinity against a panel of approximately 44 other CNS proteins tested by the PDSP …”

“…In addition, Lepovitz and Martin synthesized bioactive azaspirocycles via a novel, efficient diversity-oriented synthesis (DOS) strategy that featured a tandem sequence involving imine formation and an aza-Sakurai reaction to form the spirocyclic system, and subsequently intramolecular Pictet–Spengler cyclization with formaldehyde to build tetrahydroisoquinoline rings. Azaspirocycle 67 shows a preference for the σ 1 receptor ( K i = 8 nM) with moderate binding at σ 2 ( K i = 152 nM) and α 2A ( K i = 531 nM) receptor and weak affinity against a panel of approximately 44 other CNS proteins tested by the PDSP …”

“…Azaspirocycle 67 shows a preference for the σ 1 receptor (K i = 8 nM) with moderate binding at σ 2 (K i = 152 nM) and α 2A (K i = 531 nM) receptor and weak affinity against a panel of approximately 44 other CNS proteins tested by the PDSP. 174 Beyond that, opening the spiro scaffold of potent spirocyclic σ 1 receptor ligands represents an efficient structural modification strategy for development of novel σ 1 receptor ligands with promising biopharmaceutical properties. For example, as shown in Figure 15, (±)-haloperidol (HP) and its derivatives 69−70 may be treated as the ring-opened arylpiperidine analogues of 59.…”

Accessing spiropiperidines from dihydropyridones through tandem triflation–allylation and ring-closing metathesis (RCM)

“…Consequently, much effort is directed towards optimizing fragment collections with, in particular the elaboration of original fragments bearing spirocycles, ubiquitous molecules with unique rigidity and a three-dimensional geometry. [10][11][12] On the other hand, the piperidine ring is a common structural motif present in natural and/or synthetic products of pharmaceutical importance, and within this class of saturated nitrogen heterocycles, the spiropiperidine moiety, which is capable of exploring and spanning a large binding pocket due to its rigidly defined structure, has been considered a "privileged structure" and thus has become a sought-after motif for medicinal chemists. [13][14][15][16][17][18][19][20][21] (−)-Histrionicotoxin, a potent noncompetitive antagonist of nicotinic acetylcholine receptors, 22 (+)-nitramine 23 and ibutamoren, a potent agonist of the ghrelin receptor, 24 are examples of synthetic or natural biologically active spiropiperidines (Fig.…”

“…Consequently, much effort is directed towards optimizing fragment collections with, in particular the elaboration of original fragments bearing spirocycles, ubiquitous molecules with unique rigidity and a three-dimensional geometry. 10–12…”