The discovery of new spirocyclic muscarinic M3 antagonists

Stocks, Michael J.; Alcaraz, Lilian; Bailey, A. S.; Bowers, Keith; Donald, David K.; Edwards, Harry W.; Hunt, Fraser; Kindon, Nicholas D.; Pairaudeau, Garry; Theaker, Jill; Warner, Daniel J.

doi:10.1016/j.bmcl.2010.10.016

Cited by 11 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…88 In a search for new antagonists of the muscarinic M3 receptor, the morpholine ring in 53 was found to be crucial for activity; the corresponding 2,9-diazaspiro [5.5]undecane system (CH 2 in place of morpholine O) conferred much lower M2 and M3 activity. 89…”

Section: Spiropiperidinesmentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

View full text Add to dashboard Cite

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).

show abstract

Section: Spiropiperidinesmentioning

confidence: 99%

New and unusual scaffolds in medicinal chemistry

2011

View full text Add to dashboard Cite

show abstract

“…22 The key Boc-protected 1-oxa-4,9-diazaspiro [5.5]undecane intermediate 25 was elaborated from N-Boc-4-piperidone 21 in four steps including a Corey−Chaykovsky reaction, 23 aminolysis of the resulting epoxide 22, base-promoted condensation of vicinal amino alcohol 23 with chloroacetyl chloride, and reduction of spirocyclic lactam 24 with borane (Scheme 1). 24 The anti-inflammatory, antiallergic, and antioxidant drug fenspiride is used to treat bronchial asthma, allergic rhinitis, and other allergy symptoms within the otolaryngological system and respiratory tracts as well as respiratory manifestations of measles and the flu. 25 It is also used in symptomatic therapy for whooping cough.…”

Section: ■ Synthetic Approaches To Spirocycle Construction In Approve...mentioning

confidence: 99%

Spirocyclic Scaffolds in Medicinal Chemistry

et al. 2020

View full text Add to dashboard Cite

Spirocyclic scaffolds are incorporated in various approved drugs and drug candidates. The increasing interest in less planar bioactive compounds has given rise to the development of synthetic methodologies for the preparation of spirocyclic scaffolds. In this Perspective, we summarize the diverse synthetic routes to obtain spirocyclic systems. The impact of spirocycles on potency and selectivity, including the aspect of stereochemistry, is discussed. Furthermore, we examine the changes in physicochemical properties as well as in in vitro and in vivo ADME using selected studies that compare spirocyclic compounds to their nonspirocyclic counterparts. In conclusion, the value of spirocyclic scaffolds in medicinal chemistry is discussed.

show abstract

“…Part of this research was conducted through a discovery alliance that the company established in 2006 with Argenta [210]. A recent article disclosed the discovery of new spirocyclic muscarinic M 3 antagonists from a hit identifed from a medium-throughput screen [63]. A typical exemplar, 16, was characterized as a potent M 3 antagonist in a binding assay using [ 3 H]-Nmethyl scopolamine (pIC 50 = 8.5) with no selectivity over M 2 (pIC 50 = 8.5) .…”

Section: Future Science Groupmentioning

confidence: 99%

Inhaled Long-Acting Muscarinic Antagonists in Chronic Obstructive Pulmonary Disease

Busch-Petersen

Lainé

2011

Future Med. Chem.

View full text Add to dashboard Cite

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.

show abstract

The discovery of new spirocyclic muscarinic M3 antagonists

Cited by 11 publications

References 19 publications

New and unusual scaffolds in medicinal chemistry

New and unusual scaffolds in medicinal chemistry

Spirocyclic Scaffolds in Medicinal Chemistry

Inhaled Long-Acting Muscarinic Antagonists in Chronic Obstructive Pulmonary Disease

Contact Info

Product

Resources

About