A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity, which in turn reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effective and selective binding to target proteins compared to planar compounds with a high sp2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp3-rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.

Opportunities for Tapping into Three-Dimensional Chemical Space through a Quaternary Carbon.

Following a lipophilicity-based hypothesis, an 8-hydroxyquinolinone 2-aminoindan derived series of beta(2)-adrenoceptor agonists have been prepared and evaluated for their potential as inhaled ultralong-acting bronchodilators. Determination of their activities at the human beta(2)-adrenoceptor receptor showed symmetrical substitution of the 2-aminoindan moiety at the 5- and 6-positions delivered the targeted intermediate potency and intrinsic-efficacy profiles relative to a series of clinical reference beta(2)-adrenoceptor agonists. Further assessment with an in vitro superfused electrically stimulated guinea-pig tracheal-strip assay established the onset and duration of action time courses, which could be rationalized by considering the lipophilicity, potency, and intrinsic efficacy of the compounds. From these studies the 5,6-diethylindan analogue indacaterol 1c was shown to possess a unique profile of combining a rapid onset of action with a long duration of action. Further in vivo profiling of 1c supported the long duration of action and a wide therapeutic index following administration to the lung, which led to the compound being selected as a development candidate.

The Identification of Indacaterol as an Ultralong-Acting Inhaled β2-Adrenoceptor Agonist

A series of saligenin β2 adrenoceptor agonist antedrugs having high clearance were prepared by reacting a protected saligenin oxazolidinone with protected hydroxyethoxyalkoxyalkyl bromides, followed by removal of the hydroxy-protecting group, alkylation, and final deprotection The compounds were screened for β2, β1, and β3 agonist activity in CHO cells The onset and duration of action in vitro of selected compounds were assessed on isolated superfused guinea pig trachea Compound 13f had high potency, selectivity, fast onset, and long duration of action in vitro and was found to have long duration in vivo, low oral bioavailability in the rat, and to be rapidly metabolized Crystalline salts of 13f (vilanterol) were identified that had suitable properties for inhaled administration A proposed binding mode for 13f to the β2-receptor is presented

Synthesis and Structure—Activity Relationships of Long-acting β2 Adrenergic Receptor Agonists Incorporating Metabolic Inactivation: An Antedrug Approach

Inhaled bronchodilators, including long-acting muscarinic receptor antagonists (LAMA) and long-acting β2-adrenoreceptor agonists (LABA), are the mainstay of pharmacological treatment of stable chronic obstructive pulmonary disease (COPD). Among approved LAMA, tiotropium bromide, glycopyrronium bromide, and umeclidinium bromide are administered once daily, whereas aclidinium bromide is administered every 12 h. New LAMA are under development for COPD. Among the approved LABA, indacaterol has a 24 h duration of action, whereas salmeterol and formoterol require twice-daily administration. New once-daily LABA, including vilanterol, olodaterol, milveterol, carmoterol, and abediterol, are in development. LAMA/LABA fixed dose combinations (FDCs) provide the convenience of two bronchodilators with different mechanism of action in a single inhaler. Indacaterol/glycopyrronium, umeclidinium/vilanterol, and olodaterol/tiotropium FDCs have been approved or are under approval and are likely to become a standard pharmacological strategy for COPD. Inhaled dual-pharmacology compounds, combining muscarinic antagonism and β2-agonism (MABA) in a single molecule, potentially provide additive or synergistic bronchodilation over either inhaled antimuscarinic or β2-agonist monotherapy.

Bronchodilating Drugs for Chronic Obstructive Pulmonary Disease: Current Status and Future Trends

Discovery of olodaterol, a novel inhaled beta2-adrenoceptor agonist with a 24 h bronchodilatory efficacy.

A series of saligenin alkoxyalkylphenylsulfonamide beta(2) adrenoceptor agonists were prepared by reacting a protected saligenin oxazolidinone with alkynyloxyalkyl bromides, followed by Sonogashira reaction, hydrogenation, and deprotection. The meta-substituted primary sulfonamide was more potent than the para- and the ortho-analogues. Primary sulfonamides were more potent than the secondary and tertiary analogues. The onset and duration of action in vitro of selected compounds was assessed on isolated superfused guinea pig trachea. Sulfonamide 29b had the best profile of potency, selectivity, onset, and duration of action on both guinea pig trachea and human bronchus. Furthermore, 29b was found to have low oral bioavailability in rat and dog and also to have long duration of action in an in vivo model of bronchodilation. Crystalline salts of 29b were identified that had suitable properties for inhaled administration. A proposed binding mode for 29b to the beta(2)-receptor is presented.

Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds 24 and (R)-28 as having robust in vivo activity.

/pdf/3-5-disubstituted-indole-7-carboxamides-as-ikkb-inhibitors-3n3hfyz0ni.pdf

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

L'invention se rapporte a de nouveaux composes representes par la formule (I), a un procede de fabrication, a des compositions pharmaceutiques les contenant et a leur utilisation therapeutique, plus precisement a leur utilisation dans la prophylaxie et le traitement des maladies respiratoires.

Derives formanilides utilises en tant qu'agonistes de l'adrenorecepteur beta2

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Synthesis and structure-activity relationships of long-acting beta2 adrenergic receptor agonists incorporating arylsulfonamide groups.

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

Derives formanilides utilises en tant qu'agonistes de l'adrenorecepteur beta2