1. A compound represented by the structural formula
or a pharmaceutically acceptable salt thereof, wherein:
X1 is 1-3 substituents independently selected from the group consisting of H, alkyl, halo, \u2014CF3, \u2014OCF3, alkoxy, \u2014OH and \u2014CN;
X2 is 1-3 substituents independently selected from the group consisting of H, alkyl, halo, \u2014CF3, \u2014OCF3, alkoxy, \u2014OH and \u2014CN;
n is 0, 1 or 2; and
R and R1 are independently selected from the group consisting of H and alkyl.
2. A compound of claim 1 wherein n is 1.
3. A compound of claim 1 wherein R and R1 are each H.
4. A compound of claim 1 wherein X1 is 1 or 2 substituents independently selected from H, halo, alkyl, alkoxy and \u2014CF3.
5. A compound of claim 4 wherein X1 is 1 or 2 substituents independently selected from H, fluoro, chloro, methyl, methoxy and \u2014CF3.
6. A compound of claim 1 wherein X2 is 1, 2 or 3 substituents independently selected from H, halo, alkyl, alkoxy, \u2014CF3, \u2014OCF3 and \u2014CN.
7. A compound of claim 6 wherein X2 is 1, 2 or 3 substituents independently selected from H, fluoro, chloro, methyl, methoxy, \u2014CF3, \u2014OCF3 and \u2014CN.
8. A compound of claim 1 wherein n is 1; R and R1 are each H; X1 is 1 or 2 substituents independently selected from H, halo, alkyl, alkoxy and \u2014CF3; and X2 is 1, 2 or 3 substituents independently selected from H, halo, alkyl, alkoxy, \u2014CF3, \u2014OCF3 and \u2014CN.
9. A compound of claim 8 wherein X1 is 1 or 2 substituents independently selected from H, fluoro, chloro, methyl, methoxy and \u2014CF3, and X2 is 1, 2 or 3 substituents independently selected from H, fluoro, chloro, methyl, methoxy, \u2014CF3, \u2014OCF3 and \u2014CN.
10. A compound of claim 1 selected from the group consisting of
11. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier.
12. A pharmaceutical composition comprising a therapeutically effective amount of a combination of a compound of claim 1 and one to three other agents useful in treating Parkinson’s disease in a pharmaceutically acceptable carrier.
13. A kit comprising in separate containers in a single package pharmaceutical compositions for use in combination to treat Parkinson’s disease wherein one container comprises a pharmaceutical composition comprising an effective amount of a compound of claim 1 in a pharmaceutically acceptable carrier, and wherein, in separate containers, one or more pharmaceutical compositions each comprise an effective amount of an agent useful in the treatment of Parkinson’s disease in a pharmaceutically acceptable carrier.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method for screening for an increased likelihood of developing age-related macular degeneration (AMD) in an individual, comprising:
(a) determining levels of at least two AMD-associated protein markers (biomarkers) in a sample from the individual; and
(b) comparing the levels of the at least two biomarkers in the sample to reference levels of the at least two biomarkers characteristic of a control population of individuals without AMD,
wherein a difference in the levels of the at least two biomarkers between the sample from the individual and the control population indicates that the individual has an increased likelihood of having AMD,
wherein at least one of the biomarkers is other than a complement related protein, and
wherein at least one of the biomarkers is a complement related protein expressed at elevated levels in individuals with AMD, a complement related protein expressed at decreased levels in individuals with AMD, an immune related protein expressed at elevated levels in individuals with AMD, an immune related protein expressed at decreased levels in individuals with AMD, a structural protein expressed at elevated levels in individuals with AMD, a structural protein expressed at decreased levels in individuals with AMD, an enzyme expressed at elevated levels in individuals with AMD, an enzyme expressed at decreased levels in individuals with AMD, an immune related protein expressed at decreased levels in individuals with AMD, or an immune related protein expressed at decreased levels in individuals with AMD.
2. A method for assessing the efficacy of a treatment for age-related macular degeneration (AMD) in an individual, comprising:
(a) determining levels of at least two biomarkers in a sample from the individual either before treatment or at a first time point after treatment with an agent; and
(b) determining levels of the at least two biomarkers in a sample from the individual at a later time point during treatment or after treatment with the agent,
wherein a difference in the levels of the at least two biomarkers measured in (b) compared to (a) in which the levels of the at least two biomarkers moves closer to reference levels of the biomarkers characteristic of a control population of individuals without AMD indicates that the treatment is effective,
wherein at least one of the biomarkers is other than a complement related protein, and
wherein at least one of the biomarkers is a complement related protein expressed at elevated levels in individuals with AMD, a complement related protein expressed at decreased levels in individuals with AMD, an immune related protein expressed at elevated levels in individuals with AMD, an immune related protein expressed at decreased levels in individuals with AMD, a structural protein expressed at elevated levels in individuals with AMD, a structural protein expressed at decreased levels in individuals with AMD, an enzyme expressed at elevated levels in individuals with AMD, an enzyme expressed at decreased levels in individuals with AMD, an immune related protein expressed at decreased levels in individuals with AMD, or an immune related protein expressed at decreased levels in individuals with AMD.
3. The method of claim 1, wherein at least one of the biomarkers is a complement related protein expressed at elevated levels in individuals with AMD.
4. The method of claim 1, wherein at least one of the biomarkers is a complement related protein expressed at decreased levels in individuals with AMD.
5. The method of claim 1, wherein at least one of the biomarkers is an immune related protein expressed at elevated levels in individuals with AMD.
6. The method of claim 1, wherein at least one of the biomarkers is an immune related protein expressed at decreased levels in individuals with AMD.
7. The method of claim 1, wherein at least one of the biomarkers is a structural protein expressed at elevated levels in individuals with AMD.
8. The method of claim 1, wherein at least one of the biomarkers is a structural protein expressed at decreased levels in individuals with AMD.
9. The method of claim 1, wherein at least one of the biomarkers is an enzyme expressed at elevated levels in individuals with AMD.
10. The method of claim 1, wherein at least one of the biomarkers is an enzyme expressed at elevated levels in individuals with AMD.
11. The method of claim 1, wherein the biomarkers are immune related proteins selected from the group consisting of: gi|3337390|gb|AAC27432.1 (Haptoglobin), gi|182440|gb|AAB59530.1 (Fibrinogen gamma prime chain), gi|223002|prf\u22250401173A (Fibrin beta), gi|4558178|pdb|1QAB|D (Retinol Binding Protein), gi|28373620|pdb|1MA9|A (Vitamin D binding protein), gi|15099973|gb|AAK84185.1 (Ig heavy chain variable region (anti-thrombospondin)), gi|4838009|gb|AAD30796.1 (Ig heavy chain variable region), gi|546095|gb|AAB30327.1 (Ig heavy chain variable region (anti-histone H1 WRI-170 antibody)), gi|7428606|pir\u2225MHHUM (Ig mu chain C region, membrane-bound splice form), gi|47124562|gb|AAH70299.1 (Haptoglobin), gi|539627|pir\u2225A46546 (Leukocyte common antigen long splice form), gi|14600217|gb|AAK71298.1 (TCR beta chain Vbeta13S3), gi|11138513|gb|AAG31421.1 (FcRn alpha chain), gi|10120958|pdb|1EXU|A (MHC-related Fc Receptor), and gi|7428607|pir\u2225MHHU (Ig mu chain C region, secreted splice form).
12. The method of claim 1, wherein the biomarkers are structural proteins selected from the group consisting of: gi|178779|gb|AAA51748.1 (Apolipoprotein A-IV), P01011 (Alpha-1 antichymotrypsin), NP\u2014000925.1 (Alpha-2 antiplasmin), gi|5174525|ref|NP\u2014005900.1 (Microtubule-associated protein 1B isoform 1), gi|8928566|sp|Q02952|AK12_HUMAN (A-kinase anchor protein 12 (AKAP 250) (Myasthenia gravis autoantigen gravin)), gi|41406064|ref|NP\u2014005955.1 (Myosin, heavy polypeptide 10, non-muscle), gi|17318569|ref|NP\u2014006112.2 (Keratin 1), gi|386854|gb|AAA36153.1 (Keratin type II subunit protein), gi|1346640|sp|P35580|MYHA_HUMAN (Myosin heavy chain, nonmuscle type B), gi|1154664|emb|CAA62603.1 (Ataxia telangectasia mutated (A-T)), gi|339685|gb|AAA61181.1 (Transthyretin), gi|31615331|pdb|1HK3|A (Serum Albumin (mutant R218p)), gi|51476396|emb|CAH18188.1 (Alpha-2 macroglobulin), P06727 (Apolipoprotein A-IV), gi|51467959|ref|XP\u2014497224.1 (BMS1-like (similar to KIAA0187; ribosomal)), gi|23273927|gb|AAH35014.1 (NudC domain containing 3 (KIAA1068 protein)), P25311 (Zinc alpha-2 glycoprotein), gi|28466999|ref|NP\u2014787057.1 (ARG99 protein), gi|38649048|gb|AAH62986.1 (ZFR protein), gi|37790798|gb|AAR03501.1 (Angiotensinogen, member 8), gi|4557225|ref|NP\u2014000005.1 (Alpha-2 macroglobulin), gi|114006|sp|P067271APA4_HUMAN (Apolipoprotein A-IV), gi|7023207|dbj|BAA91880.1 (BTB and kelch domain containing 4 protein), gi|7022921|dbj|BAA91769.1 (LEPREL1 protein), gi|10437767|dbj|BAB15104.1 (Zinc finger protein 2), gi|21071030|ref|NP\u2014570602.2 (Alpha 1B glycoprotein), gi|28207863|emb|CAD62585.1 (Alpha-1 antitrypsin), gi|51471047|ref|XP\u2014370690.3 (AT rich interactive domain 2 (ARID, RFX-like)), gi|6470150|gb|AAF13605.1 (BiP protein), gi|37747855|gb|AAH59367.1 (Transferrin), gi|339486|gb|AAA61148.1 (Transferrin), gi|5817245|emb|CAB53743.1 (dJ20N2.2 (novel protein similar to tubulin, beta polypeptide 4, member Q (TUBB4Q)), gi|50363219|ref|NP\u2014001002236.1 (Alpha-1 antitrypsin, member 1), gi|28566306|gb|AAO43053.1 (Heat shock regulated-1), gi 1703025|sp|P01009 (Alpha-1 antitrypsin), gi|72059|pir\u2225NBHUA2 (Leucine-rich alpha-2-glycoprotein), gi|33469917|ref|NP\u2014877423.1 (Minichromosome maintenance protein 4), gi|6650772|gb|AAF22007.1 (Serotransferrin), gi|553788|gb|AAA61141.1 (Transferrin), and gi|47077177|dbj|BAD18510.1 (ZNF438 variant 3).
13. The method of claim 1, wherein the biomarkers are enzymes selected from the group consisting of: gi|544379|sp|P35574|GDE_RABIT (Glycogen debranching enzyme (Glycogen debrancher)), gi|34365215|emb|CAE45949.1 (TNN13-interacting kinase (FPGT-encoded)), gi 18044197|gb|AAH20197.1 (1-aminocyclopropane-1-carboxylate synthase), gi 404108|dbj|BAA03864.1 (Glutathione peroxidase), and gi 862457|dbj|BAA03941.1 (Enoyl-CoA hydratase3-hydroxyacyl-CoA dehydrogenase alpha-subunit of trifunctional protein).
14. The method of claim 1, wherein the biomarkers are proteins selected from the group consisting of: gi|7023232|dbj|BAA91891.1 (Unnamed protein product), gi|22761659|dbj|BAC11646.1 (Unnamed protein product), gi|50255295|gb|EAL18030.1 gi|34526199|dbj|BAC85198.1 (Unnamed protein product), (Hypothetical protein CNBK0510), gi|24308400|ref|NP\u2014612366.1 (Chromosome 10 open reading frame 42), gi|14625439|dbj|BAB61902.1 (KIAA1774 protein), gi|40788364|dbj|BAA34505.2 (KIAA0785 protein), and gi|51476755|emb|CAH18343.1 (Hypothetical protein).
15. A method for diagnosing age-related macular degeneration (AMD) in an individual, comprising determining a level of an AMD-associated protein marker (biomarker) in a sample from the individual and comparing the level of the biomarker in the sample from the individual to a reference level of the biomarker characteristic of a control population of individuals without AMD, where a difference in the level of the biomarker between the sample from the individual and the control population indicates that the individual has an increased likelihood of having or developing AMD.
16-19. (canceled)
20. The method of claim 15, wherein the level of the biomarker is measured by 2-dimensional difference gel electrophoresis (DIGE).
21. The method of claim 15, wherein the sample is from the blood, serum, plasma, or urine of the individual.
22. The method of claim 15, wherein the levels of a set of biomarkers is determined.
23. The method of claim 22, wherein the set of biomarkers comprises at least 2 of the biomarkers listed in Tables 4-6.
24. (canceled)