Design rationale

Nalfurafine hydrochloride is a first-in-class, nonaddictive opioid drug that is used as an antipruritic for severe itching associated with hemodialysis. This drug was launched in Japan in 2009. It has a unique morphinan structure that is rarely observed in typical and traditional opioid k agonists. The design rationale for this characteristic compound was described in a previous study [7, 28], and would be of interest to researchers in the opioid field. We will summarize the rationale in Sect. 4. 

To design a new agonist, we first attempted to remove the accessory site of nor-BNI and maintain the message and address sites. The message site of nor-BNI, a 4,5-epoxymorphinan skeleton with a cyclopropylmethyl substituent, was considered to be indispensable for opioid activity because it corresponded to the tyrosine of endogenous opioid peptides. Therefore, we postulated that the accessory site of nor-BNI was located in the address subsite of this antagonist. 

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Another issue that turns out to be very important for the sandwich-blade stiffener, but not at all important for the hat-shaped stiffener, is shear in the vertical web. Not shear in the plane of the web, but shear in the plane perpendicular to the web. This transverse shear stiffness turns out to dominate the behavior or be very important in the behavior of the sandwich blade, but simply is not addressed at all in the hatshaped stiffener. You can imagine that the transverse shearing stiffness would be more important in the sandwich blade when you consider the observation that the sandwich blade is a thick element and the hatshaped stiffener is a thin element. That is, bending and in-plane shear would dominate this response, whereas transverse shear, because the sandwich blade is thick, can very easily be an important factor in the sandwich blade. For both stiffeners, appropriate analyses and design rationale have been developed to be able to make an optimally shaped stiffener. 

Fig. 5.3 Evolution of the aPNA backbone design. Rationale for choice of amino acid in backbones 1 and 2...

Figure 20 Representation of the design rationale for two novel, bone-targeting pTyr mimics, Dmp and Dpp, relative to an x-ray structure [16] of citrate complexed with Src SH2.

A set of molecules that rank high after this process would be synthesized and subject to biological tests, i.e., in vitro enzymatic assay or binding affinity experiments, in order to confirm design rationales. Simultaneously, X-ray co-crystal structures of these ligands in complex with the target are to be determined to further corroborate modeling results. Positive results from such approaches are decisive for selection of next set of compounds for synthesis and the future directions of lead optimization. 

In our attempts to design functional clusters we have focused on substitution of the heteroanions within the Wells-Dawson structure to create nonconventional Dawson clusters incorporating two pyramidal anions. Our design rationale was based on the idea that such clusters may exhibit unprecedented properties arising from the intramolecular electronic interactions between the encapsulated anions (in this case we aimed to engineer between S S atoms of two encapsulated sulfite ions), thus providing a novel route to manipulate the physical properties of... 

The facility design rationale for maintaining process integrity, including identification and elimination of inaccessible areas that may be difficult to decontaminate, enumeration of the clean-space engineering controls, and how these controls will be applied, tested, and monitored ... 

Our group is currently developing TAN-67 (Toray), another lead opioid agonist with a characteristic 4a-aryl-decahydroisoquinoline structure. We previously discussed the design rationale and pharmacology of this compound [20, 21]. 

Design processes and their results are not sufficiently well documented. This lack of documentation prevents tracing (i) of ideas which have not been pursued further for one or the other reason, (ii) of all the alternatives studied, (iii) of the decision making processes, and (iv) of the design rationale. 

In this contribution, we use the term decision model for both a representation of design rationale [856], i.e., the decisions taken by a designer during a design process that led to a particular artifact, and for a representation of some rules or methods which can guide a designer confronted with a decision problem or which can even solve a decision problem algorithmically. 

The benefits of documenting design rationale are manifold. Explicit representations of design rationale support a consistent view among the stakeholders involved in a design project, they help to keep track of possible effects when requirements for an artifact change, and they can improve later design projects when similar problems are to be solved. 

Some aspects of design rationale, such as the work processes during the creation of a design artifact or the dependencies between different artifact versions, are covered by the domain models presented in the previous sections. This section most notably focuses on decision rationale, a term coined by Lee and Lai referring to the evaluations of alternatives, the arguments underlying the evaluations, and the criteria used for the evaluations [808]. 

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