18951-85-4Relevant articles and documents
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Overberger,C.G.,Weise,J.K.
, p. 3525 - 3532 (1968)
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Selective PPARδ Modulators Improve Mitochondrial Function: Potential Treatment for Duchenne Muscular Dystrophy (DMD)
Lagu, Bharat,Kluge, Arthur F.,Tozzo, Effie,Fredenburg, Ross,Bell, Eric L.,Goddeeris, Matthew M.,Dwyer, Peter,Basinski, Andrew,Senaiar, Ramesh S.,Jaleel, Mahaboobi,Tiwari, Nirbhay Kumar,Panigrahi, Sunil K.,Krishnamurthy, Narasimha Rao,Takahashi, Taisuke,Patane, Michael A.
, p. 935 - 940 (2018)
The X-ray structure of the previously reported PPARδ modulator 1 bound to the ligand binding domain (LBD) revealed that the amide moiety in 1 exists in the thermodynamically disfavored cis-amide orientation. Isosteric replacement of the cis-amide with five-membered heterocycles led to the identification of imidazole 17 (MA-0204), a potent, selective PPARδ modulator with good pharmacokinetic properties. MA-0204 was tested in vivo in mice and in vitro in patient-derived muscle myoblasts (from Duchenne Muscular Dystrophy (DMD) patients); 17 altered the expression of PPARδ target genes and improved fatty acid oxidation, which supports the therapeutic hypothesis for the study of MA-0204 in DMD patients.
Syntheses of optically active citronellol, citronellal, and citronellic acid by microbial oxidation and double coupling system in an interface bioreactor
Oda, Shinobu,Sugai, Takeshi,Ohta, Hiromichi
, p. 2819 - 2823 (2000)
We have already reported that (RS)-Citronellol [(RS)-1] can be optically resolved via a transacetylation with acetyl coenzyme A [acetyl-CoA] by the aid of alcohol acetyltransferase [AATFase] in Pichia kluyveri IFO 1165, which we have referred to as a double coupling system (E value, 30 to 40). In this system, although (R)-1 is obtained at over 98% ee, (S)-Citronellyl acetate [(S)-2] is prepared at 70 to 80% ee. In this article, we report on the conversion of (R)-1 to (R)-Citronellal [(R)-3] and (R)-Citronellic acid [(R)-4] in high yield without racemization by the aid of Rhodococcus equi JCM 6817 and Geotrichum candidum JCM 01747, respectively. On the other hand, the low ee of (S)-1 (78% ee) prepared via the alkaline hydrolysis of (S)-2 is converted to optically active (S)-1 and (S)-4 in high yield with a repeated double coupling system with P. kluyveri IFO 1165 and via enantioselective oxidation with Candida viswanathii IFO 10321, respectively. Thus, five optically active terpenoids related to citronellol, except for (S)-3, were efficiently synthesized via microbial transformations in an interface bioreactor.
Enantioselective oxidation of racemic citronellol with an interface bioreactor
Oda, Shinobu,Kato, Akio,Matsudomi, Naotoshi,Ohta, Hiromichi
, p. 83 - 87 (1996)
Microbial oxidation of racemic citronellol was done on the interface between a nutrient agar plate and decane (interface bioreactor). While Rhodococcus accumulated (R)-citronellal (21-80% e.e.), many yeasts accumulated (S)-citronellic acid (20-68% e.e.) as the oxidation product. For the production of (R)-citronellal and (S)-citronellic acid, Rhodococcus equi IFO 3730 and Hansenula anomala IFO 0147 were the best strains, respectively. While citronellol-oxidation in R. equi IFO 3730 was (S)-selective, citronellal-oxidation was (R)-selective. Although H. anomala had also both (S)-selective alcohol and aldehyde dehydrogenases (constitutive, NAD+-dependent), the equilibrium of the alcohol dehydrogenase shifted to reduction of citronellal. Geotrichum candidum JCM 01747 accumulated very high concentrations of citronellic acid (conversion yield 90% in 5 days or accumulation 65 mg/ml in 13 days) in spite of the strong toxicity of the acid, although the optical purity was low. For the alleviation of the toxicity of citronellol and accumulation of toxic citronellic acid, the interface bioreactor is superior to the organic-aqueous two-liquid-phase system (dispersion system).
Modulation of the Passive Permeability of Semipeptidic Macrocycles: N- And C-Methylations Fine-Tune Conformation and Properties
Boudreault, Pierre-Luc,Comeau, Christian,Derbali, Rabeb Mouna,Grandbois, Michel,Poulet, Sylvain,Ries, Benjamin,Riniker, Sereina,Sarret, Philippe,Stadelmann, Thomas,Tremblay, Jacob,C?té, Jér?me,Fr?hlich, Ulrike,Leclair, Grégoire,Marsault, éric
, p. 5365 - 5383 (2021/05/04)
Incorporating small modifications to peptidic macrocycles can have a major influence on their properties. For instance, N-methylation has been shown to impact permeability. A better understanding of the relationship between permeability and structure is of key importance as peptidic drugs are often associated with unfavorable pharmacokinetic profiles. Starting from a semipeptidic macrocycle backbone composed of a tripeptide tethered head-to-tail with an alkyl linker, we investigated two small changes: peptide-to-peptoid substitution and various methyl placements on the nonpeptidic linker. Implementing these changes in parallel, we created a collection of 36 compounds. Their permeability was then assessed in parallel artificial membrane permeability assay (PAMPA) and Caco-2 assays. Our results show a systematic improvement in permeability associated with one peptoid position in the cycle, while the influence of methyl substitution varies on a case-by-case basis. Using a combination of molecular dynamics simulations and NMR measurements, we offer hypotheses to explain such behavior.
MACROCYCLIC COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS
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Page/Page column 453; 531; 532, (2020/03/29)
Compounds, methods of use, and processes for making inhibitors of complement factor D or a pharmaceutically acceptable salt or composition thereof are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade. The inhibitors of factor D described herein reduce excessive activation of complement.
