103336-06-7Relevant articles and documents
The use of physiology-based pharmacokinetic and pharmacodynamic modeling in the discovery of the dual orexin receptor antagonist ACT-541468
Treiber, Alexander,De Kanter, Ruben,Roch, Catherine,Gatfield, John,Boss, Christoph,Von Raumer, Markus,Schindelholz, Benno,Muehlan, Clemens,Van Gerven, Joop,Jenck, Francois
, p. 489 - 503 (2017)
The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX1 andOX2) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-Ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met.
An efficient and high yield method for the N-tert-butoxycarbonyl protection of sterically hindered amino acids
Khalil, Ehab M.,Subasinghe, Nalin L.,Johnson, Rodney L.
, p. 3441 - 3444 (1996)
An important method for the N-tert-butoxycarbonyl protection of the amino functionality of α-alkylated prolines and other sterically hindered α,α-disubstituted amino acids has been developed in which the lipophilic base tetramethylammonium hydroxide is used to solubilize the otherwise insoluble zwitterionic amino acid in acetonitrile, thereby obviating the need for an aqueous medium.
COMBINATIONS OF HEPATITIS C VIRUS INHIBITORS
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Page/Page column 530, (2015/02/02)
The present disclosure is generally directed to antiviral compounds, and more specifically directed to combinations of compounds which can inhibit the function of the NS5A protein encoded by Hepatitis C virus (HCV), compositions comprising such combinations, and methods for inhibiting the function of the NS5A protein.
USE OF BENZIMIDAZOLE-PROLINE DERIVATIVES
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Page/Page column 17, (2015/06/18)
The present invention relates to compounds of the formula (I), wherein Ar1 and Ar2 are as described in the description and to their use as pharmaceuticals for the treatment of sundown syndrome. The invention also relates to the preparation of such compounds and of pharmaceutically acceptable salts thereof.
