An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

Minick, Douglas J.; Copley, Royston C. B.; Szewczyk, Jerzy; Rutkowske, Randy D.; Miller, Luke A. D.

doi:10.1002/chir.20431

Cited by 21 publications

(15 citation statements)

References 47 publications

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“…104) After re-evaluation the chiral compound, firstly reported as 1R,2R-cyclopropyl eutomer (Ϫlog K i ϭ9.9), 105) occurs to be the dextrorotatory 1S,2S-enantiomer. 106,107) Nevertheless it has been the first ligand reaching clinical trials in the treatment of attention-deficit hyperactivity disorder (ADHD). 108) Also FUB 407, an alkyl ether derivative of proxyfan, shows partial agonism in vitro (rat: Ϫlog K i ϭ8.0; EC 50 ϭ45 nM; intrinsic activity (i.a.)ϭ0.…”

Section: Imidazole-based Antagonists As Pharmacological Toolsmentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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INTRODUCTIONThe biogenic amine histamine, 2-(1H-imidazol-4-yl)-ethanamine, is produced by decarboxylation of L-histidine and is implicated in a wide range of physiological and pathophysiological functions. It is metabolised by histamine N tmethyltransferase (HMT) and mono-or diaminoxidase. Histamine is mainly acting via four distinct metabotropic histamine receptor subtypes (H 1 R-H 4 R), which have meanwhile all been cloned. Whereas antagonists for H 1 R and H 2 R subtypes have been blockbusters in therapy of allergy and ulcer, respectively, antagonists for H 3 R and H 4 R subtypes are not on the market. The recently described H 4 R seems to be involved in inflammatory and immunomodulatory processes. H 3 Rs play a central role in neurotransmission of histamine and in control of many other neurotransmitters. Several antagonists are in preclinical and some in clinical stage of development. PHARMACOLOGICAL BACKGROUND Auto-and HeteroreceptorThe H 3 R was first described in 1983 as a presynaptic autoreceptor, which mediates synthesis of histamine and inhibition of its release from histaminergic neurons in slices of rat cerebral cortex. 1) Localisation studies in rodents show a predominance in distinct regions of the central nervous system (CNS) as the H 3 R is mainly located in cerebral cortex, hippocampus, amygdala, nucleus accumbens, globus pallidus, striatum, and hypothalamus 2-5) ( Fig. 1). In addition, it is expressed in the peripheral nervous system, e.g. in gastrointestinal tract, airways and cardiovascular system. 6) Molecular aspects of the receptor, [7][8][9][10] structure-activity relationships (SAR) of ligands, [11][12][13][14][15][16][17][18][19] and pharmacology [20][21][22][23][24][25][26] have recently been resumed in many excellent reviews. This contribution focuses on the development of clinical candidates and the multifaceted potential indications targeted.In mammalian brain histaminergic neurons originate in the tuberomammillary nucleus (TMN) spreading into above mentioned brain regions, where they control histamine levels by regulation of synthesis and liberation rates 27) and modulate different neuronal systems. 28) H 3 R expression is not solely restricted to histaminergic neurons: due to its function as a heteroreceptor it can be found on colocalised neurons, and H 3 R activation modulates the release of various important neurotransmitters, i.e. dopamine, [29][30][31][32][33] acetylcholine, [34][35][36][37] norepinephrine, 38,39) serotonin, 40,41) GABA, [42][43][44] glutamate, 45) and substance P. [46][47][48] Therefore, histaminergic neurons and the cross-linkage between major neurotransmitter systems are involved in many (patho)physiological brain functions, including vigilance, memory processes, feeding behaviour and locomotor activity (Fig. 2). Interneuron cross-talk and adaptive processes seem to be important factors in H 3 Rmediated signalling. Molecular AspectsThe human histamine H 3 receptor (hH 3 R) cDNA firstly described 1999 encodes a 445 amino acid protein and belongs to the his...

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Section: Imidazole-based Antagonists As Pharmacological Toolsmentioning

confidence: 99%

Histamine H3 Receptor Antagonists Go to Clinics

Sander

Kottke

Stark

2008

Biological & Pharmaceutical Bulletin

185

118

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“…The challenges in Otamixaban AC determination are mainly due to the molecular size and flexibility, which affect both the modeling and experiment. With nine rotational bonds and a molecular weight of 446, Otamixaban is larger and more flexible than most molecules in published VCD studies [8] , [9] , [10] . To simplify the spectrum simulation of large molecules, Dunmire et al [11] replaced ketoconzole using two small chiral fragments, of 308 and 304 molecular weight.…”

Section: Introductionmentioning

confidence: 87%

“…The solvent signal was subtracted from both spectra. The measured VCD spectra were corrected for baseline artifacts by subtracting the enantiomer spectra [10] . The conformation search was carried out using Maestro 8.5 (Schrödinger, LLC).…”

Section: Methodsmentioning

confidence: 99%

Enantiomeric characterization and structure elucidation of Otamixaban

Shen

Yang

Heyse

et al. 2014

Journal of Pharmaceutical Analysis

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Otamixaban is a potent (Ki=0.5 nM) fXa inhibitor currently in late-stage clinical development at Sanofi for the management of acute coronary syndrome. Being unproductive in obtaining a suitable crystal of Otamixaban, the required enantiomeric characterization has been accomplished using vibrational circular dichroism (VCD) spectroscopy. Selected by a spectrum similarity index, the calculated spectra of several higher energy conformers were found to match well with the observed spectra. The characteristic IR bands of these conformers were also identified and attributed to the solvation effect. Combined with both the single crystal x-ray diffraction results for an intermediate and the proton NMR study, the absolute configuration of Otamixaban is unambiguously determined to be (R,R).

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“…Like proxifan, cipralisant (9), also known as GT-2331, possesses protean agonist properties [56]. Its absolute configuration was initially misattributed to be 1R,2R and was later corrected as being 1S,2S [57,58]. This compound was a corner-stone in the H 3 R field.…”

Section: Imidazole-based H 3 R Antagonistsmentioning

confidence: 96%

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

Plancher

2011

CTMC

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Since the histamine-3 receptor (H₃R) was cloned in 1999, huge efforts have been made by most of the key players in the pharmaceutical industry as well as in smaller biotech companies to increase the knowledge on this peculiar receptor, with the ultimate goal of bringing new drugs to the market. This review gives a survey on the most valuable chemical tools discovered so far and the significant pharmacological experiments on metabolic disease models published to date. Pharmacology of H₃R antagonists turns out to be very complex due to various functional activities, species selectivity, presence of H₃R isoforms and the poorly understood dichotomy in efficacy between CNS and metabolic disease models. Adding an extra layer of complexity, researchers have to cope with some recurrent safety concerns, some of them being tightly linked to the nature of the H₃R pharmacophore. Therefore this review also strives to summarize the major hurdles and some of the contradictions seen in the H₃R field, together with a brief overview of the clinical trials currently running.

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An investigation of the absolute configuration of the potent histamine H3 receptor antagonist GT‐2331 using vibrational circular dichroism

Cited by 21 publications

References 47 publications

Histamine H3 Receptor Antagonists Go to Clinics

Histamine H3 Receptor Antagonists Go to Clinics

Enantiomeric characterization and structure elucidation of Otamixaban

The Histamine H3 Receptor as a Therapeutic Drug Target for Metabolic Disorders: Status, Challenges and Opportunities

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