Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure–activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1

Sifferlen, Thierry; Boller, Amandine; Chardonneau, Audrey; Cottreel, Emmanuelle; Hoecker, Johannes; Aissaoui, Hamed; Williams, Jodi T.; Brotschi, Christine; Heidmann, Bibia; Siegrist, Romain; Gatfield, John; Treiber, Alexander; Brisbare‐Roch, Catherine; Jenck, F.; Boss, Christoph

doi:10.1016/j.bmcl.2013.12.092

Cited by 14 publications

(9 citation statements)

References 30 publications

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“…They provided interesting hits that were further optimized into potent and brain penetrant DORAs . Lately, we reported on the sulfonamide ACT‐462206 as preclinical candidate that emerged from those efforts . With the increasing knowledge on DORA binding modes and the availability of several potent DORAs in clinical trials for primary insomnia (Figure ), we decided to tackle the search for new lead structures via a scaffold‐hopping approach using 3 as a template …”

Section: Introductionmentioning

confidence: 99%

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

et al. 2016

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Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux. Compound 80 c [{(1S,6R)-3-(6,7-difluoroquinoxalin-2-yl)-3,8-diazabicyclo[4.2.0]octan-8-yl}(4-methyl-[1,1'-biphenyl]-2-yl)methanone] is a potent and selective DORA that inhibits the stimulating effects of orexin peptides OXA and OXB at both Ox1 and Ox2. In calcium-release assays, 80 c was found to exhibit an insurmountable antagonistic profile at both Ox1 and Ox2, while displaying a sleep-promoting effect in rat and dog models, similar to that of the benchmark compound suvorexant.

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Section: Introductionmentioning

confidence: 99%

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

et al. 2016

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“…Chiral benzyl amines are ubiquitous in many biologically active compounds, including the anticancer and antimalarial natural product strychnopentamine, , a class of synthetic dual orexin receptor antagonists, , and a designed inhibitor of the frataxin/ubiquitin interaction . The field of asymmetric aza-Friedel–Crafts phenol addition to ketimines − and to aryl − and propargyl aldimines to produce chiral benzylamines has been vigorously explored in recent years.…”

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confidence: 99%

Synthesis of Benzyl Amines via Copper-Catalyzed Enantioselective Aza-Friedel–Crafts Addition of Phenols to N-Sulfonyl Aldimines

Shikora

Chemler

2018

Org. Lett.

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A new copper-catalyzed enantioselective aza-Freidel-Crafts reaction between phenols and N-sulfonyl aldimines that provides chiral secondary benzylamines in good to excellent yields and excellent enantioselectivities (up to 99% ee) is disclosed. In particular, excellent scope with alkylimines was observed for the first time. The synthetic utility of the products was demonstrated in the first enantioselective synthesis of a dual orexin receptor antagonist, a compound that contains an amine-bearing stereocenter adjacent to a bis- ortho-functionalized arene.

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“…γ-lactams have attracted considerable attention due to their fascinating properties and potential applications in many fields, especially in organic synthesis and medicinal chemistry [1,2,3]. In particular, enantiomerically-pure β-aryl-γ-lactams, such as the ( R )-Rolipram 1 , considered as a cyclic derivative of GABA, which has shown antipsychotic [4,5,6], antidepressive [7,8], anti-inflammatory, immunosuppressive, and antitumor activity.…”

Section: Introductionmentioning

confidence: 99%

“…The biological activity of these compounds depends on its absolute configuration, and the ( R )-enantiomer is much more active than the ( S )-enantiomer [12,13,14,15]. Additionally, the β-aryl-γ-lactams are also important key intermediates for the synthesis of more complex compounds [1,16].…”

Section: Introductionmentioning

confidence: 99%

Efficient Synthesis of β-Aryl-γ-lactams and Their Resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen

et al. 2015

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Abstract:An efficient synthesis of enantiomerically-pure β-aryl-γ-lactams is described. The principal feature of this synthesis is the practical resolution of β-aryl-γ-lactams with (S)-Naproxen. The procedure is based on the Michael addition of nitromethane to benzylidenemalonates, which was easily obtained, followed by the reduction of the γ-nitroester in the presence of Raney nickel and the subsequent saponification/decarboxylation reaction. The utility of this methodology was highlighted by the preparation of enantiomerically-pure (R)-and (S)-Baclofen hydrochloride.

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Discovery of substituted lactams as novel dual orexin receptor antagonists. Synthesis, preliminary structure–activity relationship studies and efforts towards improved metabolic stability and pharmacokinetic properties. Part 1

Cited by 14 publications

References 30 publications

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Discovery of Highly Potent Dual Orexin Receptor Antagonists via a Scaffold‐Hopping Approach

Synthesis of Benzyl Amines via Copper-Catalyzed Enantioselective Aza-Friedel–Crafts Addition of Phenols to N-Sulfonyl Aldimines

Efficient Synthesis of β-Aryl-γ-lactams and Their Resolution with (S)-Naproxen: Preparation of (R)- and (S)-Baclofen

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