【摘 要】
：
Building on a previously disclosed PDE4 inhibitor,NVP-ABE171 (1),new compounds were synthesised with significant improvements in physico-chemical properties pharmacokinetics and therapeutic index.Thus
【机 构】
：
Novartis Institutes for Biomedical Research UK
【出 处】
：
中国上海第七届国际新药发明科技年会
论文部分内容阅读
Building on a previously disclosed PDE4 inhibitor,NVP-ABE171 (1),new compounds were synthesised with significant improvements in physico-chemical properties pharmacokinetics and therapeutic index.Thus,NVP-ABE171 was a low solubility (pH 6.8=0.002g/L; pH l=0.00004g/L) compound with highly variable bioavailability (rat BAV=10% +/-5%).Rational optimisation ofphysico-chemical properties led to the synthesis of several development candidates with much improved solubility (>10g/L) and pharmacokinetic parameters (rat BAV 65-97%).Potency at the PDE4 enzyme was retained (IC50<100nM) and excellent in vivo efficacy was demonstrated in several models of inflammation.Screening for toxicological side effects was carried out in the rat and the ferret model of emesis,and led to the nomination of the compound with the greatest therapeutic ratio for further development.
其他文献
Several natural antimicrobial peptides including cecropins,magainins and melittins have been found to kill cancer cells.However,their efficacy may not be adequate for their development as anticancer a
Competitive enzyme inhibitors are of interest mainly for medicinal applications.Structure of inhibitor,the extent of its interaction with the enzyme,and the way the enzyme responds to the inhibitor ar
Lipopolysaccharide (LPS) outer membrane component of Gram-negative bacteria involved in a variety of biochemical and pathological processes including Gram-negative sepsis,acute lung injury (ALI) and a
ADME-tox study has become an essential part of drug discovery research,aiming to build the necessary druggabilities ("drug-like" properties) into drug candidates with higher successful probabilities i
We have developed a series of N-Salicylidene-based L-amino acids as chiral auxiliaries for chiral vanadyl(V) methoxide complex synthesis.In all cases except the 3,5-di-tert-butyl analog,they all exist
The huge majority of currently used drugs is based on "organic" compounds not containing metal atoms.However,metal complexes offer interesting opportunities for the development of novel drugs due to t
Natural products play a crucial role in pharmaceutical industry as they are important resources for the discovery of novel drug leads.One strategy to expand the structural diversity of natural product
Paclitaxel (Taxol(R)),a microtubule inhibitor,has been widely used as a chemotherapeutic agent.However,the injectable taxol formulation to overcome poor solubility has created serious side effects tha
Coenzyme Q 10 (CoQ 10),a lipophilic nutritional supplement,has increased in popularity in many countries because of growing evidence of therapeutic benefits and an excellent safety profile.Improved ce
Physiologically based pharmacokinetic (PBPK) modelling is a simulation tool that has a huge impact in the Lead optimization stage.In PBPK modelling,each tissue is represented as a compartment that has