Data processing: measuring – calibrating – or testing – Measurement system in a specific environment – Biological or biochemical
Reexamination Certificate
2001-01-17
2003-05-13
Brusca, John S. (Department: 1631)
Data processing: measuring, calibrating, or testing
Measurement system in a specific environment
Biological or biochemical
C702S027000, C435S004000
Reexamination Certificate
active
06564152
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to novel screening methods which enable the selection of neurokinin-1 (NK-1) receptor antagonist compounds (e.g., a substance P receptor antagonist) which do not possess significant inhibitory potency towards cytochrome P450 enzymes, in particular, CYP2D6. The present invention also relates to a method of generating a pharmacophore model of NK-1 receptor antagonist compounds which do not possess significant inhibitory potency towards CYP2D6. The invention also relates to methods for the discovery of molecules that are NK-1 receptor antagonist compounds which do not possess significant inhibitory potency towards the CYP2D6 enzyme. The invention also relates to pharmaceutical compositions comprising a NK-1 receptor antagonist compound that does not possess significant inhibitory potency towards CYP2D6 as identified by methods of the invention. The invention further relates to the uses of a NK-1 receptor antagonist compound identified by the methods of the invention for the manufacture of medicaments and for the treatment of a condition, a disorder or a disease in a mammal for which such an NK-1 antagonist receptor compound is therapeutically useful.
In the field of drug development, the developer of pharmaceutical substances must investigate the potential for clinically significant negative drug—drug interactions in the situations where more than one drug may be co-administered to a patient. There is a also significant need in the field of drug development to ascertain the potential existence of these drug—drug interactions prior to commencing any investigation into drug development. The identification of the strong potential usefulness of a chemical compound as early as possible in vitro saves considerable investment of time and resources.
Antagonists for the human NK-1 receptor are likely to be therapeutically useful in treating nausea, asthma, migraine, arthritis, post-operative pain (Takeuchi et al.,
J. Med. Chem.,
41: 3609-3623, 1998) and depression (Kramer et al.,
Science,
281: 1640-1645, 1998). It would therefore be advantageous to be able to ascertain whether or not a useful therapeutic compound will inhibit any drug metabolizing enzymes involved in the clearance of other co-administered pharmaceuticals. There is a critical need for efficient, rapid and reliable methods to select promising candidates in drug discovery that demonstrate potency towards the NK-1 receptor, but not towards drug metabolizing enzymes, such as the cytochrome P450 series.
Drug—drug interactions involving cytochrome P450 enzymes (CYPs) are an important factor in the question of whether a new chemical entity will survive through to the development stage. CYPs are members of a large superfamily of heme-thiolate proteins involved in the metabolism of endobiotics and xenobiotics across eukaryotes and procaryotes. (Nelson et al.,
Pharmacogenetics,
6: 1-42, 1996). The clinical relevance of CYPs are their central role in drug metabolism. They are present in all human tissues and may be inhibited by the co-administration of competing xenobiotics of the same enzyme. (Wrighton et al.,
Toxicologic Pathology,
23: 199-208, 1995). Much less is known about the endogenous functions of CYPs, except for their role in steroid metabolism and recent postulations about their roles in neurotransmitter metabolism (Hiroi et al.,
Biochem. Biophys. Res. Commun.,
249: 838-43, 1998) and signaling pathways (Chan et al.,
Proc. Natl. Acad. Sci.,
95: 10459-10464, 1998). The current understanding of the structural requirements of the CYP active site are presently limited to homology models using P
450
CAM
, P
450
TERP
and P450
eryF
. (Lewis et al.,
Xenobiotica,
27: 319-340, 1997).
One of the human CYPs, CYP2D6, has been well studied. The polymorphic enzyme, CYP2D6, represents only approximately 1.5% of the total human hepatic P450 (Shimada et al.,
J. Pharmacol
. &
Exp. Pharmacol.,
270: 414-423, 1994), yet participates in the metabolism of over 30% of clinically prescribed drugs (Lewis et al., supra.) including many which have a narrow therapeutic index. (Spatzenegger and Jaeger,
Drug Metabolism Reviews,
27: 397-417, 1995; Wu et al.,
Biochem. Pharmacol.,
53: 1605-1612, 1997; Lewis et al., supra.). The clinical relevance of CYP2D6 is notable as approximately 7% of Caucasians are poor metabolizers of CYP2D6 substrates while 1% are ultrarapid metabolizers of CYP2D6 substrates. (Brosen,
Ther. Drug Monitoring,
18: 393-396, 1996). If a drug, which is an inhibitor of CYP2D6, is co-administered with a drug which has CYP2D6-mediated biotransformation as its major clearance mechanism, there is the potential danger of the occurrence of a clinically hazardous event depending on the concentration of the drugs at the enzymes in question.
Therapeutic drug monitoring of CYP2D6 modulators is costly and impacts on health care costs; thus minimizing interactions with CYP2D6 is advantageous to the patient and the entire health care system. Ultimately, knowledge of CYP2D6 inhibitory potential may impact on whether a drug will be co-administered with drugs which are known substrates of CYP2D6. Accordingly, the ability to predict the likelihood of a molecule being a CYP2D6 inhibitor early in the discovery process allows for the more efficient synthesis of suitable candidate molecules without the structural features which cause undesirable inhibition. A means of screening for drugs which do not have significant interaction with the CYP2D6 enzyme is therefore desirable.
Present technologies have centered around the use of in vitro testing using human liver microsomes or recombinant CYPs and a known catalytic probe for CYP2D6 such as bufuralol. However, the possible volume of in vitro studies is often limited by equipment and materials cost, incubation volume and the rate of analytical determination. Alternatives to in vitro techniques as a preliminary screen, enabling the selection of compounds for later study in vitro, would need to be fast, cost effective and reliable.
One such alternative, embraced by the present invention, is the use of computational quantitative structure activity relationship (QSAR) modeling techniques as a screening device for inhibitory potency towards CYP2D6. In the past, computational techniques have led to the production of some computer generated substrate templates, pharmacophores as well as homology models of the active site of CYPs. A pharmacophore model generated by SYBYL has been derived from CYP2D6 inhibitors of bufuralol 1′-hydroxylation as a selective probe for generating K
i
values. (Strobl et al.,
J. Med. Chem.,
36:1136-1145, 1993). This inhibitor pharmacophore model suggested that a positive charge on a nitrogen atom and a flat hydrophobic region extending to 7.5 Å virtually perpendicular along the N-H axis are requirements for inhibitory activity. (Strobl et al., Id.). Very recently, attempts at pharmacophore modeling of diverse inhibitors using CATALYST™ have been described which were used prospectively or retrospectively to predict inhibitor binding affinity for CYP2D6 (Ekins et al.,
Pharmacogenetics,
9: 477-489, 1999).
To date, however, closely related molecules from a single therapeutic class have not been used to model the CYP2D6 active site from the point of view of inhibitory activity. There have only been QSAR models from other CYPs generated using a single therapeutic class of compounds, such as quinolones for CYP1A2 (Fuhr et al.,
Mol. Pharmacol.,
43: 191-199, 1993) or warfarin analogs for CYP2C9 (Jones et al.,
Drug Metabolism
&
Disposition,
24: 1-6, 1996).
Approaches towards modeling the common features of substrates and inhibitors of human CYPs in general from data generated in vitro have been recently shown using a CATALYST™ pharmacophore approach (Ekins et al., supra; Ekins et al.,
J. Pharmacol.
&
Exp. Ther.,
288: 21-29, 1999; Ekins et al.,
J. Pharmacol.
&
Exp. Ther.,
290: 429-438, 1999; Ekins et al.,
J. Pharmacol.
&
Exp. Ther.,
291: 424-433, 1999), comparative molecular field analysis (
Ekins Sean
Smith Bill J.
Brusca John S.
Ginsburg Paul H.
Nissenbaum Israel
Pfizer Inc
Richardson Peter C.
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