The structural optimization of a family of modular, enantiopure β-amino alcohol ligands with a common 2-amino-2-aryl-1,1-diphenylethanol skeleton, whose stereogenicity was introduced through the ...Jacobsen epoxidation of 1,1-diphenyl-2-arylethylenes, has led to the identification of a small set of optimal catalysts with enhanced activity and enantioselectivity in the addition of alkylzinc and arylzinc reagents to aldehydes. Criteria for the discrimination between apparently analogous, highly enantioselective ligands are proposed.
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ1 receptor antagonists. Modification of a high-throughput screening hit originated a series of ...piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, 18g, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.
A series of enantiopure ligands based on the aminoindanol scaffold, but differing in regio‐ and stereochemistry has been synthesized. These ligands have been conveniently derivatized and their ...catalytic efficiency in different enantioselective reactions has been screened to determine privileged candidates with respect to regio‐ and stereochemistry for each considered process. The nature of the amino substituent has been optimized for specific applications and this has led to the development of an efficient method for the preparation of bulky bicyclic amines by reductive amination.
The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3H)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) are ...reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3H)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the R enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities. Final modification of the central scaffold to reduce lipophilicity provided the pyrido4,3-dpyrimidin-4(3H)-one 16RR, which showed high selectivity for Cavα2δ-1 versus Cavα2δ-2, probably linked to its improved analgesic efficacy-safety ratio in mice over pregabalin.
A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ
receptor antagonists. Modification of a high-throughput screening hit originated a series of ...piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified,
, showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.
(S)-2-(R)-Fluoro(phenyl)methyloxirane is a new, synthetic, yet enantiopure, chiral resolution reagent, readily obtained from enantiopure (2S,3S)-phenylglycidol, that reacts with a variety of α-chiral ...primary and secondary amines in a straightforward manner through a regioselective ring-opening. Diastereomeric products are easily identified and quantified by 19F, 1H, and 13C NMR and by HPLC, which makes this fluorinated compound a most versatile reagent for the analysis of scalemic mixtures of amines.
PDF
