Discovery of Isoxazole Analogues of Sazetidine-A as Selective α4β2-Nicotinic Acetylcholine Receptor Partial Agonists for the Treatment of Depression

Abstract

Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenalin are not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogs that interact with α4β2-nAChR as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary ADMET studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450 related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

“…While the potency at α4β2 subtypes is excellent, compound 7 also behaved as an agonist at the α7 subtype with a K i value of 136 nM. Substituents at the 5-position of the pyridine core were found to be beneficial for the selectivity for α4β2 over α7 and ganglionic nAChRs, consistent with our own findings employing sazetidine-A analogs[8-11, 13]. In our continued efforts to develop highly selective α4β2-nAChR partial agonists with improved stability, we herein report preliminary SAR findings focused on the incorporation of the diazepane and diazabicycloheptane moieties into our cyclopropyl- or isoxazolylpyridine ether scaffolds.…”

“…Besides α4, β2, or α7, other unidentified subunits may also be present. Details are provided in the Experimental Section. c K i values for nicotine are taken from the PDSP Assay Protocol Book. d ND: not detected. e NA: not active, defined as < 50% inhibition of binding in the primary assay at 10 μM. f K i values for 3, 4, and 1 are from the literature[8, 9]. …”

“…Previously our group reported the discovery of highly potent and selective α4β2*-nAChR partial agonists containing a cyclopropyl- or isoxazolylpyridine ether scaffold as versatile building blocks for achieving selectivity for α4β2- over α3β4-nAChRs[8-11]. Compounds 3 and 4 bind potently to α4β2-nAChRs ( K i < 1 nM) but not to α3β4*- ( K i > 10 4 nM) and α7-nAChRs ( K i > 10 4 nM) or other neurotransmitter receptors and transporters widely distributed throughout the CNS, while possessing favorable ADMET profiles.…”

Synthesis of 3,4,5-Trisubstituted Isoxazoles through Gold-Catalyzed Cascade Cyclization-Oxidative Alkynylation and Cyclization-Fluorination of 2-Alkynone O-Methyloximes

“…Column chromatography (40:1 hexane/EtOAc) afforded 4i (36.7 mg, 32%) as a yellow solid, 5 (10 mg, 16%) as a yellow solid, 6 (15. 4 …”

“…1 is an important scaffold frequently found in many natural products and biologically active compounds such as analgesics, 2 antibiotics, 3 antidepressants, 4 and anticancer agent. 5 It has also been used as a synthetic intermediate, building block and chiral ligand in organic synthesis.…”