Liabilities improvements

Compliance Limits liability Improves image Better performance Fewer head- aches ... 

Reduce Soil Intrusion None Reduced disposal cost and liability Improved treatment plant operation Low administrative burden Modest cost... 

Other Titles - The Clean Air Act Amendments of 1990 continue the federal acid rain research program and contain several provisions relating to research, development and air monitoring. They also contain provisions to provide additional unemployment benefits through the Job Training Partnership Act to workers laid off as a consequence of compliance with the Clean Air Act. The Act also contains provisions to improve visibility near National Parks and other parts of the country. Strict enforcement of the Clean Air Act Amendments is the driving force behind pollution abatement. Non-compliance is simply not an option, since there are both financial and criminal liabilities that outweigh any benefits derived from a business. 

Frame PSM in terms of their interests. People pay more attention to information that is relevant to them, than to items of general or academic interest. For example, "PSM provides a cost-effective means of improving our company s safety performance" addresses two senior executive concerns corporate earnings and exposure to liability. The discussion is framed in terms of the listener s interest it also focuses on results. 

These can be achieved through reduced downtime, consolidating safety-related activities, improving operations information, facilitating process design improvements, minimizing exposure to liability, and improving customer satisfaction. 

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). 

Fluorine has been used to modulate the basicity of amines which may lead to an improvement in brain exposure. Recently, the discovery of a series of a4(32 nicotinic acetylcholine receptor (nAChR) potentiators as possible treatment for Parkinson s disease and schizophrenia was were disclosed [40]. Optimization of isoxazole 40 included the bioisosteric replacement of the central amide by an imidazole ring. Introduction of a fluorine at the 6-position of the phenyl ring provided compound 41. This compound had excellent potency but was determined to be a substrate for P-gp (efflux ratio >10). In an attempt to reduce amine basicity and decrease the efflux propensity, the 4-fluoropiperidine 42 was identified which retained potency and had significantly reduced P-gp efflux liability (efflux ratio 1). CNS penetration of 42 was observed in rodents following intraperitoneal (IP) treatment at 5mg/kg and showed a brain concentration of 6.5 gM. 

Houtsmuller EJ, Pant RV, Eissenberg TE, Henningfleld JE, Stitzer ML (2002) Flavor improvement does not increase abuse liability of nicotine chewing gum, Pharmacol Biochem Behav 72 559-568... 

At lead selection, after which typically more chemistry effort is invested, the selected compounds can be profiled in a broader (secondary) panel of assays, hopefully confirming the selective nature of the leads. If this is the case, spot checking in the primary panel through the optimization phase may be sufficient to ensure selectivity is retained while the required potency at the primary target is achieved. If the selected leads are still rather promiscuous, or certain individual unwanted liabilities remain, these should be monitored by testing in the primary panel (or in additional individual assays) and improved upon during lead optimization. Tfie broader panel can then be applied again to the selected development candidates for a final check and these may even be extended further to additional specialized panels for added security. 

---