Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-07
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • No compounds in this series

    2022-01-18

    No compounds in this series showed any appreciable activity at GlyT2 and can thus be considered GlyT1-selective. For the GlyT2 IC was >20μM. To determine CNS penetration of -(2-(azepan-1-yl)-2-phenylethyl)-benzenesulfonamides, select compounds were evaluated in a cassette CNS exposure screen in male Sprague-Dawley rats. Compounds , , and were selected based on their potencies and relative solubilities. Appreciable whole SB 204990 and plasma concentrations were observed one hour post subcutaneous injection. Brain–plasma ratios ranged from 1.6 to 2.1, indicating good partitioning across the blood–brain barrier and distribution into brain tissue. In conclusion, starting from hit 4-chlorosulfonamide , the azepane amine was identified as the only heterocyclic replacement more potent than a piperidine. Solubility was quickly identified as a physical property to be monitored and, if possible, improved. An analysis of various aromatic and non-aromatic sulfonamides identified phenyl sulfonamides as having the best balance between in vitro potency and solubility. Substitution of the - and/or -positions of the phenyl sulfonamide with hydrophobic groups was preferred, with 4-trifluoromethyl sulfonamide offering the most potent analog. Subsequent exploration of phenyl ring substitution of the 2-amino-2-phenylethanamine scaffold of identified the 2-methoxy group () as a way to improve both uptake inhibition and solubility. To evaluate the CNS penetration of -(2-(azepan-1-yl)-2-(2-methoxy-phenylethyl)-benzenesulfonamides, exemplar 4-trifluoromethyl, 4-chloro, and 3-chloro-4-fluoro-sulfonamides were analyzed via in vivo pharmacokinetic studies in Sprague-Dawley rats. All three compounds demonstrated good distribution into brain tissue and favorable brain–plasma ratios. Acknowledgments
    Introduction Preclinical and clinical data indicate that N-methyl-d-aspartate (NMDA) receptor hypofunction is a primary pathophysiology in schizophrenia [1], [2], [3]. Thus, NMDA receptor antagonists mimic the positive, negative, and cognitive symptoms of schizophrenia, exacerbate symptoms in schizophrenics, and can trigger the re-emergence of symptoms in stable patients [4], [5]. These findings suggest that enhancing NMDA function may provide therapeutic benefit in schizophrenia. NMDA receptor function can be enhanced by glycine, an obligate coagonist at the strychnine-insensitive (GlyB) site on the receptor channel complex, which acts by increasing the frequency of channel opening [6]. In addition to glycine, d-serine has also been proposed to function as an endogenous coagonist at the GlyB site [7]. Increasing endogenous synaptic glycine concentrations can be achieved by inhibition of the glycine transporter type 1 (GlyT1), which functions to maintain glycine concentrations below saturating levels at the NMDA receptor [8], [9]. GlyT1 (SLC6A9) is a Na+/Cl−-dependent transporter and exists as several isoforms (GlyT1a–d) [9], which cannot be distinguished pharmacologically (unpublished observations). GlyT1 is highly expressed in brainstem and cerebellum and is also present in forebrain regions [10]. As GlyB site agonists and the GlyT1 inhibitors sarcosine and RG1678 improved symptoms in schizophrenics without producing significant adverse effects [2], [3], [11], [12], [13], [14], considerable efforts have been focused on developing GlyT1 inhibitors as a treatment for schizophrenia [15], [16]. Preclinically, GlyT1 inhibitors or genetic disruption of neuronal GlyT1 in the forebrain elevated glycine concentration in brain, potentiated NMDA activity in brain slices, and improved prepulse inhibition (PPI) and cognition in behavioral models [17], [18], [19], [20], [21], [22]. However, the dual role of GlyT1 as the regulator of glycine concentration at both excitatory glutamatergic NMDA and inhibitory glycinergic synapses raises the possibility of side effects associated with GlyT1 inhibition. The strychnine-sensitive glycine receptor (GlyA) and GlyT1 are co-localized in the caudal brainstem, and play a critical role in control of respiration and motor function [23], [24]. Consistent with its localization, homozygous GlyT1 deletion in mice was lethal due to motor deficits and respiratory depression, similar to the symptoms of nonketotic hyperglycinemia in humans [23], [25]. At doses that elevate brain glycine concentrations, sarcosine-derived GlyT1 inhibitors produced adverse effects in rodents including compulsive, purposeless walking, comparable to obstinate progression (OP) [26], respiratory depression, lateral recumbency, and ataxia [10], [16], [27]. While the precise mechanism is unknown, it has been suggested that sustained elevation of extracellular glycine in caudal brain areas is causal, raising concerns regarding the safety of GlyT1 inhibitors [10]. It has been postulated that adverse behaviors may arise from GlyT1 inhibitors that contain a sarcosine motif and/or possess a noncompetitive mode of inhibition [28], suggesting that different chemotypes or modification of other properties of the pharmacophore may result in less severe side effects without affecting antipsychotic efficacy.