MaxiPost

Highly enantioselective fluorination of unprotected 3-substituted oxindoles: one-step synthesis of BMS 204352 (MaxiPost).[Pubmed:23030737]

J Org Chem. 2012 Oct 19;77(20):9148-55.

The catalytic enantioselective fluorination of N-H-free 3-substituted oxindoles was accomplished by a Sc(III)/N,N'-dioxide complex. Under mild reaction conditions, a series of 3-aryl- and 3-alkyl-3-fluoro-2-oxindoles were obtained in excellent yields (up to 98%) and enantioselectivities (up to 99% ee) by using N-fluorobisbenzenesulfonimide (NFSI) as the fluorination agent. MaxiPost was synthesized efficiently in 81% yield with 96% ee.

Anxiolytic effects of Maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels.[Pubmed:15814569]

J Pharmacol Exp Ther. 2005 Jul;314(1):282-92.

Neuronal Kv7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal Kv7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing Kv7 channel subtypes, MaxiPost (BMS-204352) exerted positive modulation of all neuronal Kv7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the Kv7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha1beta2gamma2s and alpha2beta2gamma2s) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal Kv7 channel subtypes allowed us to assess the potential role of Kv7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive Kv7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the Kv7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal Kv7 channels are a target for developing novel anxiolytics.

Potassium ion channel openers, Maxipost and Retigabine, protect against peripheral salicylate ototoxicity in rats.[Pubmed:25937133]

Hear Res. 2015 Sep;327:1-8.

Sodium Salicylate (SS) reliably induces a sensorineural hearing loss and tinnitus when administered in high doses. Recent animal modeled studies indicate that potassium channel openers such as MaxiPost and Retigabine (RTG) can block SS- or noise-induced tinnitus respectively; however, the origins and mechanisms are poorly understood. Since SS blocks the same potassium channels that MaxiPost and RTG open, we postulated that these drugs might influence peripheral auditory function. To test this hypothesis MaxiPost or RTG were administered alone or in combination with SS in rats. When administered alone, MaxiPost and RTG had no effect on distortion product otoacoustic emissions (DPOAE) or compound action potentials (CAPs). However when MaxiPost or RTG were administered with SS, MaxiPost prevented the SS-reduced CAP amplitudes at high frequencies (>/=20 kHz) and RTG prevented SS-reduced CAP amplitudes at low frequencies (MaxiPost and RTG can protect against peripheral damage and therefore reduce the incidence of tinnitus.

Effects of the potassium ion channel modulators BMS-204352 Maxipost and its R-enantiomer on salicylate-induced tinnitus in rats.[Pubmed:21640740]

Physiol Behav. 2011 Oct 24;104(5):873-9.

Currently, there are no effective pharmacological therapies for chronic tinnitus despite a number of efforts from clinical studies and more recently, studies in animals using compounds to enhance endogenous inhibition or reduce central hyperactivity. The purpose of the current study was to evaluate the therapeutic efficacy of a novel anxiolytic with potassium channel activity in suppressing salicylate induced tinnitus in animals. Kv7 potassium channels are present in the peripheral and central auditory system where they are believed to modulate neural activity. MaxiPost, a compound which attenuates hyperexcitability via positive modulation of Kv7.2-Kv7.5 channels, was administered to rats with behavioral evidence of salicylate induced tinnitus. Tinnitus was measured using our previously established animal model, Schedule Induced Polydipsia Avoidance Conditioning, a paradigm where rats were conditioned to drink only during quiet and suppress drinking in the presence of sound. Salicylate alone significantly suppressed licks in quiet but had no effect on licks in sound; results consistent with the presence of tinnitus. MaxiPost at 10 mg/kg suppressed behavioral evidence of tinnitus as it completely reversed salicylate's suppression of licks in quiet. Unexpectedly, the R-enantiomer of MaxiPost, R-MaxiPost, which has no anxiolytic effects and negatively modulates Kv7.2-Kv7.5, also suppressed behavioral evidence of tinnitus. Our original hypothesis was that Kv7.2-Kv7.5 channels might play a key role in tinnitus generation and that MaxiPost but not R-MaxiPost would suppress tinnitus; however, it appears that a shared mechanism between MaxiPost and R-xMaxiPost, such as inhibition of Kv7.1 channels or activation of BK channels or some novel mechanism common to both compounds, underlies salicylate induced tinnitus as both compounds completely abolished behavioral evidence of tinnitus in a dose-dependent manner. Further studies with specific BK channel agonists/antagonists are necessary to determine the contribution of these channels to other forms of tinnitus or determine novel targets that could be related to tinnitus.

One man's side effect is another man's therapeutic opportunity: targeting Kv7 channels in smooth muscle disorders.[Pubmed:22880633]

Br J Pharmacol. 2013 Jan;168(1):19-27.

Retigabine is a first in class anticonvulsant that has recently undergone clinical trials to test its efficacy in epileptic patients. Retigabine's novel mechanism of action - activating Kv7 channels - suppresses neuronal activity to prevent seizure generation by hyperpolarizing the membrane potential and suppressing depolarizing surges. However, Kv7 channels are not expressed exclusively in neurones and data generated over the last decade have shown that Kv7 channels play a key role in various smooth muscle systems of the body. This review discusses the potential of targeting Kv7 channels in the smooth muscle to treat diseases such as hypertension, bladder instability, constipation and preterm labour.

Catalytic enantioselective fluorination of oxindoles.[Pubmed:16028916]

J Am Chem Soc. 2005 Jul 27;127(29):10164-5.

We have developed a highly efficient catalytic enantioselective fluorination of oxindole derivatives. In the presence of a catalytic amount of chiral Pd complex 2 (2.5 mol %), various substrates, including aryl- and alkyl-substituted oxindoles, were fluorinated in a highly enantioselective manner (up to 96% ee). In addition, when R was a hydrogen atom, enantioselective fluorination followed by solvolysis gave a monofluorinated ester with up to 93% ee. To our knowledge, this is the first example of catalytic enantioselective fluorination of oxindoles.

Flindokalner (BMS-204352) is a potassium channel modulator. Flindokalner is a positive modulator of all neuronal Kv7 channel subtypes expressed in HEK293 cells. Flindokalner is also a large conductance calcium-activated K channel (BKca) positive modulator. Flindokalner shows a negative modulatory activity at Kv7.1 channels (Ki=3.7 μM), and acts as a negative modulator of GABAA receptors. Flindokalner shows anxiolytic efficacy in vivo.

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