Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists

Lainé, Dramane I.; McCleland, Brent W.; Thomas, Sonia; Neipp, Christopher E.; Underwood, Brian; Dufour, Jeremy; Widdowson, Katherine L.; Palovich, Michael R.; Blaney, Frank E.; Foley, James J.; Webb, Edward F.; Luttmann, Mark A.; Burman, Miriam; Belmonte, Kristen E.; Salmon, M

doi:10.1021/jm801601v

Cited by 21 publications

(17 citation statements)

References 28 publications

(56 reference statements)

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“…45) is a very potent, slowly reversible antagonist of the muscarinic M3 receptor and has a very long duration of bronchoprotection in vivo. 134 There are numerous alkaloids containing the tropane (8-methyl-3-azabicyclo[3.2.1]octane) skeleton. The 3-azabicyclo-[3.2.1]octane system is also present in the potent synthetic agonist 79 which is selective for the a3and a6-nicotinic receptors; 135 the system is also found in some potent dual V 1a /V 2 vasopressin antagonists.…”

Section: Azabicyclooctanesmentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

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Contemporary medicinal chemistry faces diverse challenges from several directions, including the need for both potency and specificity of any therapeutic agent; the increasingly demanding requirements of low toxicity shown across all patients treated; and the need for novelty in intellectual property, given the extensive use of benzenoid and heteroaromatic ring systems in numerous patents. Increasingly, such challenges are being met by a shift to new and/or unusual ring systems (scaffolds) that lie outside the field of (hetero)aromatic systems. This critical review surveys a necessarily limited selection of currently atypical scaffolds, chiefly drawn from the literature of the last three years, that have found application in medicinal chemistry, some being present in agents with therapeutic potential while others are found in agents already in clinical use (163 references).

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Section: Azabicyclooctanesmentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

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“…As opposed to aclidinium, the GSK compounds are not esters, but rather contain a diphenylhydroxymethyl or diphenylacetonitrile moiety attached to the 4-position of the quinuclidine ring. The most potent of these was compound 9 (FiguRe 2), which displayed a pA 2 value of 10.5 against the M 3 receptor [59]. Computational docking studies using a homology model of the M 3 receptor were used to explain the observed SAR of this class of compounds.…”

Section: Other Compounds In Preclinical or Clinical Developmentmentioning

confidence: 99%

“…Computational docking studies using a homology model of the M 3 receptor were used to explain the observed SAR of this class of compounds. In addition to its high potency, kinetic washout studies at the human M 3 cloned receptor and in human bronchus showed that 9 had a slow reversibility profle [59]. The pharmacokinetic profle of 9 was characterized by low oral bioavailability and high plasma clearance.…”

Section: Other Compounds In Preclinical or Clinical Developmentmentioning

confidence: 99%

Inhaled Long-Acting Muscarinic Antagonists in Chronic Obstructive Pulmonary Disease

Busch-Petersen

Lainé

2011

Future Med. Chem.

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In 2002, the first long-acting muscarinic antagonist, tiotropium bromide (Spiriva(®)), was launched as a once-daily bronchodilating agent for the treatment of chronic obstructive pulmonary disease. Since then, there has been intense discovery research activity in this area and, currently, several alternative inhaled long-acting muscarinic antagonists are reported under clinical development by several pharmaceutical companies. This article will review the current inhaled development candidates, as well as literature reports of the most significant preclinical chemical series specifically designed as inhaled antimuscarinic agents.

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“…The LAMAs also exhibit anti‐inflammatory effects and anti‐remodeling effects such as the inhibition of mucus gland hypertrophy . One example is umeclidinium bromide ( 1 , Scheme ), a potent muscarinic acetylcholine receptor antagonist identified in 2009 . This molecule was approved by the US Food and Drug Administration (FDA) at the end of 2013 as a highly effective active pharmaceutical ingredient (API) for the maintained treatment of stable COPD …”

Section: Introductionmentioning

confidence: 99%

A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide

et al. 2018

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A more sustainable process for the synthesis of the long-acting muscarinic acetylcholine antagonist umeclidinium bromide is described. Specifically, we report the synthesis of ethyl 1-(2-chloroethyl)-4-piperidinecarboxylate, a key intermediate in the preparation of umeclidinium bromide, in good yields using triethylamine, as well as the identification and characterization of the by-product formed in this reaction. This new method of synthesis leads to an improvement in yield over that of previously reported protocols using potassium carbonate as base (65.6 % versus 38.6 %). Moreover, in the final synthetic step of the process to obtain umeclidinium bromide, we were able to replace the use of toxic solvents (acetonitrile/chloroform) with water. The use of this green solvent allowed precipitation of the active pharmaceutical ingredient (API) from the reaction medium with high purity and in high yield. Overall, we have developed a more efficient and environmentally friendly process for the synthesis of the umeclidinium bromide API with a higher overall yield (37.8 % versus previously reported overall yield of 9.7 %).

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Discovery of Novel 1-Azoniabicyclo[2.2.2]octane Muscarinic Acetylcholine Receptor Antagonists

Cited by 21 publications

References 28 publications

New and unusual scaffolds in medicinal chemistry

New and unusual scaffolds in medicinal chemistry

Inhaled Long-Acting Muscarinic Antagonists in Chronic Obstructive Pulmonary Disease

A More Sustainable Process for Preparation of the Muscarinic Acetylcholine Antagonist Umeclidinium Bromide

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