Optimization compound profile

These so-called Pareto-based techniques do not force consolidation over multiple criteria in advance and aim to return a representation of the set of optimal compounds. They support discussion between team members who may have different views on the downstream impacts of different risk factors perhaps, for example, one team member may know that there is a reliable biomarker for one potential side-effect. This would then mean that assessing this risk need not consume much development time and cost, and the risk factor can have a reduced weighting within the target product profile being evolved by the team. 

Unity resulted in 4234 hits. After application of several filters and clustering of the remaining 1975 molecules, compounds from 18 of the 27 clusters were screened in Xenopus oocytes. One compound with an IC50 of 5.6pM belonged to a new class of Kvl.5 blockers and exhibited a favorable pharmacokinetic profile. After further optimization, compound 73 (IC50 = 0.7pM Fig. 16.9) resulted, with good oral bioavailability in rats [145]. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

As such, VolSurf affords much structural information of use in designing compounds with optimal permeability profile, and in defining an ideal property space in similarity searches. 

Fig. 14.9 Individual components of multidimensional optimization. This approach requires experimental compound profiling against key properties, which should be done on a designed compound subset to maximize information with a minimum number of molecules. These data are used to derive models for key properties, which are applied during the next design cycle. The results then led to augmented models. The process is characterized by a tight integration of in vitro and in silico tools for profiling compound series to guide chemical optimization.

By using this targeted approach, one can limit compound-profiling activities to areas of high likelihood of BMT and optimize the cost-effectiveness of such screening. 

The number of compounds in D can be determined using PCA or can be known beforehand. In any case, the number obtained must not be considered a fixed parameter, and resolution of the system considering different numbers of components is a usual and recommended practice. In contrast to ITTFA, MCR-ALS uses complete C- or ST-type matrices during the ALS optimization instead of optimizing the profiles one at a time. The core of the method consists of solving the following two least-squares problems under appropriately chosen constraints ... 

A series of phenoxyphenyl sulfone A-formylhydroxy-lamines was identified that contained potent and selective matrix metalloproteinase (MMP) inhibitors. Compound 27 displayed remarkable selectivity for both MMP-2 and MMP-9 over the undesired MMP-1. Unfortunately, 27 had no oral bioavailability. SAR modifications revealed that diol 28 maintained ideal selectivity, but suffered from low plasma exposure in monkey and a short in vivo half-life. Further modification showed that acetonide 29 had the desired selectivity for MMP-2 and MMP-9 and also displayed an optimal PK profile in monkeys with a plasma concentration 18-fold higher than 28. Oral bioavailabilities for 29 were >70% in rat, dog, and monkey. 

So far, no single in vitro assay has been generally accepted as the most promising preliminary screening. Many antirheumatic drugs have shown activity in a variety of the in vitro assays mentioned above. Obviously the spectrum of a compound and not the activity in any single assay should be emphasized. At the present time, the optimal biochemical profile of an ideal agent remains shrouded in the unknown. 

The extruder screw consists of three primary zones feed zone, compression zone, and metering zone. In the feed zone located under the extruder feed box, the screw flights are well spaced to optimize compound flow. The mbber is passed into a compression zone, where the compound is heated through shear then into a metering zone, where the compound is further heated to reduce viscosity and finally into the die for profile formation. 

In the lead optimization phase, in vitro ADMET assays play in particular an important role to monitor, how potential liabilities evolve and to drive their optimization to an overall acceptable compound profile. 

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