39251-56-4Relevant academic research and scientific papers
Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
Hillisch, Alexander,Gericke, Kersten M.,Allerheiligen, Swen,Roehrig, Susanne,Schaefer, Martina,Tersteegen, Adrian,Schulz, Simone,Lienau, Philip,Gnoth, Mark,Puetter, Vera,Hillig, Roman C.,Heitmeier, Stefan
supporting information, p. 12574 - 12594 (2020/11/13)
Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and apply these for the selection of a lead series with the highest possibility of achieving oral bioavailability. In our design, we relied on protein structure knowledge to address potency and identified a small window of favorable physicochemical properties to balance absorption and metabolic stability. Protein structure information on the pregnane X receptor helped in overcoming a persistent cytochrome P450 3A4 induction problem. The selected compound series was optimized to a highly potent, neutral, non-prodrug thrombin inhibitor by designing, synthesizing, and testing derivatives. The resulting optimized compound, BAY1217224, has reached first clinical trials, which have confirmed the desired pharmacokinetic properties.
STEREOCHEMISTRY OF NITROGEN HETEROCYCLES. 68. STEREOCHEMISTRY OF 2,5-DIMETHYL-4-PIPERIDONE, 2,5-DIMETHYL-4-PIPERIDOL, AND THEIR N-BENZOYL DERIVATIVES
Litvinenko, G. S.,Voronenko, L. A.,Krasnomolova, L. P.
, p. 796 - 804 (2007/10/02)
The isomers of 1-benzoyl-2,5-dimethyl-4-piperidone were obtained and equilibrated (89.8percent cis 10.2percent trans isomer, preferred conformations 2a, 5e, and 2a, 5a).The position of the equilibrium between the isomers of 2,5-dimethyl-4-piperidone was determined by two independent methods (89.5percent trans 10.5percent cis isomer).The differences in the free energies of the isomers, the conformational energy of the β-CH3 group, and the energy of syn-axial 1,3-interaction between the CH and the unshared electron pair were calculated; the decrease in the conformational energy of the β-methyl group in the series of piperidine (1.6), 4-piperidone (1.47), and N-acyl-4-piperidone (1.28 kcal/mole) was explained by the successive weakening of the repulsive interaction between the β-CH3 group and the n-pair of the nitrogen as a result of the flattening of the ring and of the conjugation between the free electron pair of the nitrogen and the ? electrons of the acyl carbonyl group.The last previously unknown fourth isomer of 2,5-dimethyl-4-piperidol, which exists in the 2e,4a,5a conformation, was obtained by the reduction of cis-1-benzoyl-2,5-dimethyl-4-piperidone followed by debenzoylation.In contrast to the secondary amine, its N-benzoyl- and N-benzyl-substituted derivatives exists in the alternative 2a,4e,5e conformation.The configurations and conformations of the isomers were determined by means of the IR and NMR spectra.
