EP1513522A2 - Verfahren zur behandlung von mit einem edg-rezeptor assoziierten krankheitszuständen - Google Patents

Verfahren zur behandlung von mit einem edg-rezeptor assoziierten krankheitszuständen

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Publication number
EP1513522A2
EP1513522A2 EP03710713A EP03710713A EP1513522A2 EP 1513522 A2 EP1513522 A2 EP 1513522A2 EP 03710713 A EP03710713 A EP 03710713A EP 03710713 A EP03710713 A EP 03710713A EP 1513522 A2 EP1513522 A2 EP 1513522A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
substituted
heteroaryl
edg
cιo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03710713A
Other languages
English (en)
French (fr)
Inventor
Geetha Shankar
David Solow-Cordero
Juliet V. Spencer
Charles Gluchowski
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SRI International Inc
Original Assignee
SRI International Inc
Stanford Research Institute
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Filing date
Publication date
Application filed by SRI International Inc, Stanford Research Institute filed Critical SRI International Inc
Publication of EP1513522A2 publication Critical patent/EP1513522A2/de
Withdrawn legal-status Critical Current

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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
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Definitions

  • the present invention relates generally to methods of modulating biological activity mediated by an Edg-2, an Edg-3, an Edg-4 or an Edg-7 receptor. More specifically, the present invention provides compounds and compositions, which may be used to selectively modulate, e.g., antagonize an Edg-2, an Edg-3, an Edg-4 or an Edg-7. The present invention also provides methods for making these compounds.
  • Lysophospholipids include compounds such as lysophosphatidic acid ("LPA”), sphingosine- 1-phosphate (“SIP”), lysophosphatidylcholine and sphingosylphosphorylcholine and are important second messengers that can activate particular cell surface transmembrane G-protein coupled receptors known as endothelial gene differentiation (“Edg”) receptors.
  • LPA lysophosphatidic acid
  • SIP sphingosine- 1-phosphate
  • Edg endothelial gene differentiation
  • S1P1 (Edg 1), S1P3 (Edg 3), S1P2 (Edg 5), and S1P5 (Edg 8) belong to one structural cluster and LPA1 (Edg 2), LPA2 (Edg 4) and LPA3 (Edg 7) are members of a second structural cluster (Goetzl, B. J., and Lynch, K. R. 2000, Ann. N. Y. Acad. Sci. 905:1-357).
  • Edg-1 human Edg-1, GenBank Accession No. AF233365
  • Edg-3 human Edg-3, GenBank Accession No. X83864
  • Edg-5 human Edg-5, GenBank Accession No. AF034780
  • Edg-6 human Edg-6, GenBank Accession No. AJ000479
  • Edg- 8 human Edg-8, GenBank Accession No. AF3 17676 receptors are activated by SIP, while LPA activates Edg-2 (human Edg-2, GenBank Accession No., U78 192), Edg-4 (human Edg-4, GenBank Accession Nos. AF233092 or AFO1 1466) and Edg-7 (human Edg-7, GenBank Accession No.
  • the present invention addresses these and other needs by providing compounds that modulate the Edg-4 (LPA2) receptor (e.g, human Edg-4, GenBank Accession Nos. AF233092 or AFO1 1466). Such compounds preferably selectively bind or otherwise modulate the Edg-4 receptor.
  • LPA2 Edg-4
  • the present invention provides methods for modulating (antagonizing or agonizing) Edg-4 receptor mediated biological activity.
  • the present invention also provides methods for using Edg-4 modulators (antagonists or agonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer; acute lung diseases, adult respiratory distress syndrome ("AERDS"), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury, (e.g., transcorneal freezing or cutaneous bums) and cardiovascular diseases (e.g., ischemia) in a subject in need of such treatment or prevention.
  • diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer
  • acute lung diseases such as asthma, surface epithelial cell
  • the present invention provides compounds and compositions that can, for example, be used in modulating Edg-4 receptor mediated biological activity or treating or preventing diseases such as those mentioned above.
  • the present invention still further provides methods for synthesizing the compounds.
  • the present invention provides a method of modulating an Edg-4 receptor mediated biological activity in a cell. A cell expressing the Edg-4 receptor is contacted with an amount of an Edg-4 receptor modulator sufficient to modulate the Edg-4 receptor mediated biological activity.
  • the present invention provides a method for modulating Edg-4 receptor mediated biological activity in a subject.
  • an amount of of the Edg-2 receptor effective to modulate the Edg-2 receptor mediated biological activity is administered to the subject.
  • the present invention also provides compounds (agonists or antagonists) that modulate Edg-4 receptor mediated biological activity.
  • the agonists or antagonists are compounds of structural formula (I) and can be utilized as part of the methods of the present invention:
  • R] is hydrogen, alkyl, substituted alkyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkylarylamino, substituted alkylarylamino, amino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylamino, substituted arylamino, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl sulfonylamino or substituted sulfonylamino;
  • A is NR 2 , O or S
  • R is hydrogen, alkyl or substituted alkyl
  • B and C are independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl.
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (IV):
  • each of Ri, R 2 , R , R or R 5 is independently -H, -halo, -NO , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 ,
  • each R 5 and Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(Ci-C, 0 )alkyl(Ci-Cio)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C 1 -C 10 )alkyl,
  • C 10 )alkyl ), -CO 2 (C,-C 10 )alkyl, -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl,
  • X and Y are each independently C or N; and Z is O, S, C or N, wherein if Z is O or S, then R is an electron pair;
  • R t and R can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 2 and R can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring; and R 3 and R can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • the modulator is a compound of structural formula
  • each of Ri, R 2 , R 3 , R 4 or R 5 is independently -H, -halo, - ⁇ O 2 , -CN, -OH,
  • each R( is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • the agonists or antagonists are compounds of structural formula (VI):
  • each of Ri, R 2 , R 3 , R4 or R 5 is independently -H, -halo, -NO 2 , -CN, -OH,
  • R 5 or R ⁇ is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C 1 -C 10 )alkyl(C,-C 10 )alkyl, -O(d-C 10 )alkyl, -C(O)(d-C 10 )alkyl,
  • X, Y and Z are independently O, S, C or N, wherein if X, Y or Z is O or S, R ⁇ is an electron pair; Ri and R 2 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 4 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • Ri and R 5 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 5 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (VII):
  • each of Ri, R 2 , R 3 , R 4 , R 5 , R 7 or R 8 is independently -H, -halo, -NO 2 , -CN,
  • each R 5 or Rs is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • C 10 )alkyl or -SO 2 NH 2 ;
  • m is independently an integer ranging from 0 to 8;
  • p is independently an integer ranging from 0 to 5;
  • X is O, S, C or N, wherein if X is O or S, Ri is an electron pair;
  • Y and Z are independently N or C, wherein if Y or Z is N, R ⁇ and R 2 are each an electron pair.
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (VIII):
  • each of Ri, R 2 , R 3 , R , R 5 , R 7 , R 8 , R 9 or R ⁇ 0 is independently -H, -halo, -NO 2 , -CN, -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C ⁇ 0 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(d-C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5
  • each Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • o cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -phenyl, naphthyl, -(C 3 -C 10 )heterocycle, -CO 2 (CH 2 ) m (C ⁇ -C ⁇ o)alkyl, -CO 2 (CH 2 ) m H, -NHC(O)NH(d-C ⁇ 0 )alkyl, -OC(O)O(C ⁇ - C 10 )alkyl, or -SO 2 NH 2 ; m is independently an integer ranging from 0 to 8; p is independently an integer ranging from 0 to 5; and X and Y are independently O, S or N, wherein if X or Y is O or S, R and R JO are an electron pair.
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (IX):
  • each of Ri, R 2 , R 3 , Rj , R 5 , R 7 , R 8 , R or Rio is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C 1 -C, 0 )alkyl, -(C 2 - C ⁇ o)alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicy
  • each R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C 10 )alkyl(C ⁇ -C 10 )alkyl, -O(d-C 10 )alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl,
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (X):
  • each of R,, R 2 , R 3 , R4 , R 5 or R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 ,
  • each R 5 or R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • R] and R 2 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 2 and R 3 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 4 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 4 and R 7 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • the agonists or antagonists that can be utilized as part of the methods of the present are compounds of structural formula (XI):
  • each of Ri, R 2 , R 3 , R , R 5 , R 7 or R 8 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O CH,) ⁇ , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -C(OH)R 5 , -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C ⁇ 4 )
  • each R 6 is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C 1 -C 10 )alkyl(C,-C ⁇ o)alkyl, -O(C 1 -C ⁇ 0 )alkyl, -C(O)(C 1 -C 10 )alkyl, -C(O)NH(CH 2 ) m (d-C, 0 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((d-C, 0 )alkyl(d- C,o)alkyl), -CO 2 (C,-do)alkyl, -(C,-C 10 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl,
  • Ri and R 2 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 2 and R 3 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 3 and R 4 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring; and R 7 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 8 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring; and Ri and Rs can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (XII):
  • each of Ri, R 2 , R 3 , R 4 , R 5 or R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -C(OH)R 5 , -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C ⁇ o)alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C M )bic
  • each R 5 or R is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C 1 -C 10 )alkyl(C ⁇ -C 1 o)alkyl, -O(C 1 -C 1 o)alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (d-C 10 )alkyl, -OCF 3 , -benzyl, -C ⁇ 2 (CH 2 ) m CH((C,-C ⁇ o)alkyl(C ⁇ - C 10 )alkyl), -CO 2 (C ⁇ -C,o)alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl,
  • R 3 or R 4 can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring; Ri or R 2 can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring; and R 2 or R 4 can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring.
  • the present invention provides compounds that modulate the Edg-7 (LPA3) receptor (e.g., human Edg-7, GenBank Accession No. AF127138). Such compounds selectively bind or otherwise modulate the Edg-7 receptor.
  • LPA3 Edg-7
  • the compounds that can, for example, be used to modulate Edg-7 receptor mediated biological activity or to treat or prevent diseases such as those discussed above.
  • the agonists or antagonists are compounds of structural formula (XIII) and can be utilized in the methods of the present invention:
  • X is NR 3 , S or O
  • Ri is hydrogen, alkyl, substituted alkyl, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, amino, carbamoyl, substituted carbamoyl, oxo, thiono or -NR 4 ;
  • R 2 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkyloxy, substituted alkyloxy, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, amino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
  • R 3 is hydrogen, alkyl, substituted alkyl, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylsulfonyl, substituted arylsulfonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroalkyl;
  • R 4 is alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl substituted heteroaryl, cycloheteroalkyl, substituted cycloheteroalkyl, and
  • R 5 and R are independently hydrogen, alkyl, substituted alkyl, acylamino, substituted acylamino, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl or optionally along with the carbon to which they are attached form an aryl, substituted aryl, cycloalkyl, substituted
  • the present invention also provides compounds (agonists or antagonists) that can, for example, be used to modulate Edg-7 receptor mediated biological activity or to treat or prevent diseases such as those discussed above.
  • the agonists or antagonists can be utilized in the methods of the present invention and are compounds of structural formula (XIV):
  • each of Ri, R 2 , R 3 R 4 and R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C-C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C l0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C] 4 )bicycloalkyl, -(C 5 -C ⁇ 0 )cyclo
  • each R 5 and R 6 is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, ⁇ (0,-0 10 )3 ⁇ 1(0,-0 10 )3 ⁇ 1, -0(0,-0 10 )3 !, -C(O)(C ⁇ -C 10 )alkyl, -C(O)NH(CH 2 ) m (C,-C, 0 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C,-C ⁇ 0 )alkyl(C,- C,o)alkyl), -CO 2 (C,-C, 0 )alkyl, -(C ⁇ -C, 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C -C ⁇ o)cycl
  • R 3 R 4 and R 7 can also be an electron such that when two groups are on adjacent carbon atoms they form a double bond; two R groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the agonists or antagonists can be utilized in the methods of the present invention and are also compounds of structural formula (XV):
  • each of R,, R 2 , R 3 R 4 and R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C ⁇ 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(d-C ⁇ o)cycloalkyl, -(C 8 -C ⁇
  • R 3 is -H, -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -(C ⁇ )heteroaryl, -(C 5 -C ⁇ o)heteroaryl, -naphthyl, -(C
  • each R 5 and R* is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C, 0 )alkyl(C,-C,o)alkyl, -O(C,-C ⁇ 0 )alkyl, -C(O)(C,-C ⁇ o)alkyl,
  • the present invention provides methods for modulating Edg-7 receptor mediated biological activity.
  • the present invention also provides methods for using Edg-7 modulators (i.e., agonists and antagonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer; acute lung diseases, adult respiratory distress syndrome ("ARDS"), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury, (e.g., transcorneal freezing or cutaneous burns) and cardiovascular diseases (e.g., ischemia) in a subject in need of such treatment or prevention.
  • ARDS adult respiratory distress syndrome
  • the present invention provides compounds and compositions for use in modulating Edg-7 receptor mediated biological activity or treating or preventing diseases such as those mentioned above as well as methods for synthesizing the compounds.
  • the present invention provides a method of modulating
  • the present invention provides a method for modulating
  • the present invention provides compounds that modulate the Edg-2 (LPAl) receptor (e.g., human Edg-2, GenBank Accession No., U78192). Such compounds preferably selectively bind or otherwise modulate the EDG-2 receptor.
  • the present invention provides methods for modulating (antagonizing or agonizing) Edg-2 receptor mediated biological activity.
  • the present invention also provides methods for using Edg-2 modulators (agonists and antagonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer; acute lung diseases, adult respiratory distress syndrome ("ARDS"), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury, (e.g., transcorneal freezing or cutaneous burns) and cardiovascular diseases (e.g., ischemia) in a subject in need of such treatment or prevention.
  • diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer
  • acute lung diseases such as ovarian cancer, peritoneal cancer, end
  • the present invention provides compounds and compositions that can, for example, be used in modulating Edg-2 receptor mediated biological activity or treating or preventing diseases such as those mentioned above.
  • the present invention still further provides methods for synthesizing the compounds.
  • the present invention provides a method of modulating an Edg-2 receptor mediated biological activity in a cell. A cell expressing the Edg-2 receptor is contacted with an amount of an Edg-2 receptor modulator sufficient to modulate the Edg-2 receptor mediated biological activity.
  • the present invention provides a method for modulating Edg-2 receptor mediated biological activity in a subject.
  • an amount of a modulator of the Edg-2 receptor effective to modulate the Edg-2 receptor mediated biological activity is administered to the subject.
  • the present invention also provides compounds (agonists or antagonists) that modulate Edg-2 receptor mediated biological activity.
  • the agonists or antagonists are compounds of structural formula (XX) and can be utilized as part of the methods of the present invention: (XX)
  • P, Q and R are independently aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl.
  • the agonists or antagonists can be utilized as part of the methods of the present invention and are compounds of structural formula (XXIII):
  • each of R,, R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C, 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C,o)alkynyl, -(C 3 -C,o)cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 5 -C ⁇ o)cyclo alkenyl
  • each of R 5 and R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C ⁇ o)alkyl(C,-C,o)alkyl, -O(C ⁇ -C,o)alkyl, -C(O)(C,-C,o)alkyl, -C(O)NH(CH 2 ) m (C,-C,o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C,-C, 0 )alkyl(C ⁇ -
  • Ri and X or R 2 and Y can together form a double bond.
  • the agonists or antagonists are compounds that can be utilized as part of the methods of the present invention and are of structural formula (XVII):
  • each of Ri and R 2 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C, 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C, 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C,o)cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 5 -C,o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -(C 5 -C,o)heteroaryl, -naphthyl, -(C
  • each R 5 and R 6 is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • each of Ri and R 2 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -NH(aryl), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-do)alkyl, -(C 2 -C, 0 )alkenyl, -aryl, -(C 2 -C,o)alkynyl, -(C 3 -C, 0 )cycloalkyl, -(C 3 -C ⁇ o)cycloalkyl(aryl), -(C 8 -C, 4
  • each R 5 and R 6 is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • R, and R 2 can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6- membered aromatic ring; two R 6 groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the present invention provides compounds that modulate the S1P3 or Edg-3 receptor (e.g. human Edg-3, GenBank Accession No. X83864). Such compounds preferably selectively bind or otherwise modulate the Edg-3 receptor. In one embodiment, the present invention provides methods for modulating
  • Edg-3 receptor mediated biological activity The present invention also provides methods for using Edg-3 modulators (i.e., agonists or antagonists) in treating or preventing diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer; acute lung diseases, adult respiratory distress syndrome ("ARDS”), acute inflammatory exacerbation of chronic lung diseases such as asthma, surface epithelial cell injury, (e.g., transcorneal freezing or cutaneous burns) and cardiovascular diseases (e.g., ischemia) in a subject in need of such treatment or prevention.
  • diseases such as ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer
  • acute lung diseases
  • the present invention provides methods for using Edg-3 modulators (i.e., agonists or antagonists) in treating or preventing disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephrosis, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia.
  • Edg-3 modulators i.e., agonists or antagonists
  • disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular ne
  • Edg-3 agonists and antagonists can be used to treat vascular occlusive disorders.
  • activation of Edg-3 receptors by using an Edg-3 agonist will result in increased vasoconstriction which is beneficial in conditions such as migraine headaches.
  • Inhibition of Edg-3 by an Edg3 antagonist will be beneficial in conditions such as a stroke, a subarachnoid hemorrhage, or a vasospasm such as a cerebral vasospasm.
  • the present invention provides a method of modulating an Edg-3 receptor mediated biological activity in a cell.
  • a cell expressing the Edg-3 receptor is contacted with an amount of an Edg-3 receptor modulator sufficient to modulate the Edg-3 receptor mediated biological activity.
  • the present invention provides a method for modulating an Edg-3 receptor mediated biological activity in a subject. In such a method, an amount of a modulator of the Edg-3 receptor effective to modulate an Edg-3 receptor mediated biological activity is administered to the subject.
  • the present invention also provides compounds and compositions for use in modulating (i.e., agonizing or antagonizing) Edg-3 receptor mediated biological activity or treating or preventing diseases such as those mentioned above as well as methods for synthesizing the compounds.
  • the Edg-3 receptor modulators are compounds of structural formula (XXXI) :
  • n 0 or 1 ;
  • o 0, 1, 2, 3 or 4;
  • X is C, NR 7 O or S
  • Y is C, NR 8 O or S
  • R is either absent or hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylamino, substituted arylamino, arylsulfonyl, substituted arylsulfonyl, carboxy, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamin
  • R 2 , R 3 and R 4 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylamino, substituted arylamino, arylsulfonyl, substituted arylsulfonyl, carboxy, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalky
  • each R 5 is independently, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylsulfonyl, substituted arylsulfonyl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substitute
  • R and R 8 are independently absent, hydrogen, alkyl, substituted alkyl, acyl or substituted acyl.
  • Edg-3 receptor modulators are compounds of structural formula (XXXII):
  • each of R,, R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C,o)cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 5 -C,o)cycloalkenyl, -
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C, 0 )alkynyl,
  • each R 5 and R is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C,o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C,-C,o)alkyl, -C(O)(C,-C,o)alkyl, -C(O)NH(CH 2 ) m (C,-C 10 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C,-C,o)alkyl(C,- C, 0 )alkyl), -CO 2 (C,-C, 0 )alkyl, -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C,o)cyclo
  • X is O, S, C(R 5 )(R 5 ) or N(R 5 );
  • Ri, R 2 or R 3 taken in combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • Edg-3 receptor modulators are compounds of structural formula (XXXIII):
  • each of R,, R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C 10 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C ]0 )alkynyl, -(C 3 -C,o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C, 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C, 4 )bicycloalkyl, -(C 5 -C,o)cycloalkenyl, -(C 5 )heteroaryl, -(C )heteroaryl, -(C 5 -C,o)heteroaryl, -naphthyl, -(C 3
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(d-C ⁇ o)alkyl(C,-C,o)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C,-C,o)alkyl, -C(O)NH(CH 2 ) m (d-C, 0 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C ⁇ -C, 0 )alkyl(C ⁇ - C ⁇ o)alkyl), -CO 2 (C ⁇ -C ⁇ o)alkyl, -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C -C ⁇ o)cycloal
  • Ri, R 2 or R 3 taken in combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6-membered aromatic ring; two R 6 groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • Fig. 1 illustrates the selectivity of 101 for the Edg-4 receptor
  • Fig. 2 illustrates a dose response curve for Edg-4 antagonists 101, 103 and 105;
  • Fig. 3 illustrates a dose response curve for 101 and LPA in HTC rat hepatoma cells transfected with human Edg-4 receptors
  • Fig. 4 illustrates a dose response curve for 101 in OV202 human ovarian cancer cells
  • Fig. 5 illustrates a dose response curve for 101 in CaOV-3 human ovarian cancer cells
  • Fig. 6 illustrates the inhibition of VEGF production by 101 in CaOV-3 human ovarian cancer cells
  • Fig. 7 illustrates the inhibition of IL-8 production by 101 in CaOV-3 human ovarian cancer cells
  • Fig. 8 illustrates the inhibition of LPA-stimulated proliferation by 101 in CaOV-3 human ovarian cancer cells
  • Fig. 9 illustrates the inhibition of LPA-stimulated chemotaxis by 103 in
  • Fig. 10 illustrates the lack of inhibition of S IP-stimulated migration by 103 in human umbilical vein endothelial cells
  • Fig. 11 illustrates a dose response inhibition curve of LPA induced calcium mobilization by the Edg-4 antagonists 101, 103, 107 and 113 in HTC rat hepatoma cells transfected with human Edg-4;
  • Fig. 12 illustrates a dose response inhibition curve of LPA induced calcium mobilization by the Edg-4 antagonists 101, 103, 107 and 113 in HTC rat hepatoma cells transfected with pooled rat Edg-4 clones
  • Fig. 13 illustrates a dose response inhibition curve of LPA induced calcium mobilization by the Edg-4 antagonists 101, 103, 107 and 113 in HTC rat hepatoma cells transfected with pooled mouse Edg-4 clones;
  • Figure 14 illustrates the efficacy of 101 in suppressing the tumor growth as tested by in vivo Z-chamber study
  • Figure 15 illustrates a dose response inhibition curve of LPA induced calcium mobilization by the Edg-4 antagonist 125 in HTC cells;
  • Figure 16 illustrates a dose response inhibition curve of LPA induced calcium mobilization by the Edg-4 antagonist 125 in CaOV-3 cells
  • Fig. 17 illustrates the selectivity of 701 for the Edg-7 receptor
  • Fig. 18 illustrates the inhibition of LPA-stimulated calcium mobilization by 703 in HT-1080 human fibrosarcoma cells
  • Fig. 19 illustrates the selectivity of 201 for the Edg-2 receptor
  • Fig. 20 illustrates the selectivity of 203 for the Edg-2 receptor
  • Fig. 21 illustrates the inhibition of LPA-stimulated calcium mobilization in immortalized ovarian surface epithelial cells by Edg-2 antagonist 203;
  • Fig. 22 illustrates the effects of 203 on the inhibition of cAMP production by LPA
  • Fig. 23 illustrates the inhibition of LPA-stimulated calcium mobilization in A431 human epitheloid carcinoma cells by Edg-2 antagonist 201 ;
  • Fig. 24 illustrates the inhibition of LPA-stimulated calcium mobilization in A431 human epitheloid carcinoma cells by Edg-2 antagonists 201 and 203, but not Edg-4 antagonist, 101;
  • Figure 25 illustrates the selectivity of 301 for the Edg-3 receptor
  • Figure 26 illustrates the inhibition of S IP-stimulated calcium mobilization by
  • “Compounds of the invention” refers generally to any modulator of the LPA2 or Edg-4 receptor (e.g. human Edg-4, GenBank Accession Nos. AF23 3092 or AFOl 1466) and includes any Edg-4 receptor modulator encompassed by generic formulae disclosed herein and further includes any species within those formulae whose structure is disclosed herein.
  • “Compounds of the invention” also refers generally to any modulator of the Edg-7 receptor (e.g. human Edg-7, GenBank Accession No. AF 127138) encompassed by generic formulae disclosed herein and further includes any species within those formulae whose structure is disclosed herein.
  • Compounds of the invention also refers generally to any modulator of the LPAl or Edg-2 receptor (human Edg-2, GenBank Accession No., U78192) and includes any Edg-2 receptor modulator encompassed by generic formulae disclosed herein and further includes any species within those formulae whose structure is disclosed herein.
  • Compounds of the invention also refers generally to any modulator of the S1P3 or Edg-3 receptor (e.g., human Edg-3, GenBank Accession No. X83864) and includes any Edg-3 receptor modulator encompassed by generic formulae disclosed herein and further includes any specific Edg-3 receptor modulator within those formulae whose structure is disclosed herein.
  • the compounds of the invention may be identified either by their chemical structure and/or chemical name.
  • the chemical structure is determinative of the identity of the compound.
  • the compounds of the invention may contain one or more chiral centers and/or double bonds and therefore, may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers or diastereomers.
  • the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the illustrated compounds including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan.
  • the compounds of the invention may also exist in several tautomeric forms including, but not limited to, the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds.
  • the compounds of the invention also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature.
  • isotopes examples include, but are not limited to, 2 H, 3 H, ,3 C, 14 C, 15 N, ,8 0, 17 0, 31 P, 32 P, 35 S, 18 F and 36 C1. Further, it should be understood that when partial structures of the compounds of the invention are illustrated, brackets indicate the point of attachment of the partial structure to the rest of the compound.
  • Composition of the invention refers to at least one compound of the invention and a pharmaceutically acceptable vehicle, with which the compound is administered to a patient.
  • the compounds of the invention are administered in isolated form, which means separated from a synthetic organic reaction mixture.
  • Alkyl refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne.
  • Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop- 1 -en- 1-yl, prop-l-en-2-yl, prop-2- en-l-yl (allyl), cycloprop-1-en-l-yl; cycloprop-2-en-l-yl, prop-1-yn-l-yl, prop-2-yn- 1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-l-yl, 2-methyl- propan-2-yl, cyclobutan-1-yl, but- 1 -en- 1-yl, but-l-en-2-yl, 2-methyl-prop-l -en- 1-yl, but-2-en-l-
  • alkyl is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” are used. Preferably, an alkyl group comprises from 1 to 20 carbon atoms.
  • Alkanyl refers to a saturated branched, straight-chain or cyclic alkyl group derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane.
  • Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl fiec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yi, etc.; and the like.
  • Alkenyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene.
  • the group may be in either the cis or trans conformation about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop- 1 -en- 1-yl, prop-l-en-2-yl, prop-2-en-l-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-l-yl; cycloprop-2-en-l-yl; butenyls such as but- 1 -en- 1-yl, but-l-en-2-yl, 2-methyl-prop-l - en-l-yl, but-2-en-l-yl , but-2-en-l-yl, but-2-en-2-yl, buta-l,3-dien-l-yl, buta-1,3- dien-2-yl, cyclobut-1-en-l-yl, cyclobut-l-en-3-yl, cyclobuta-l,3-dien-l-yl, etc.; and the like.
  • Alkynyl refers to an unsaturated branched, straight-chain or cyclic alkyl group having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop- 1-yn- 1-yl, prop-2-yn- 1-yl, etc.; butynyls such as but-1-yn-l-yl, but-l-yn-3-yl, but-3-yn-l-yl, etc and the like.
  • Acyl refers to a radical -C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as defined herein.
  • Representative examples include, but are not limited to formyl, acetyl, cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.
  • Acylamino refers to a radical -NR'C(O)R, where R' and R are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.
  • Representative examples include, but are not limited to, formylamino, acetylamino, cylcohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino and the like.
  • Alkylamino means a radical -NHR where R represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cydohexyl amino and the like.
  • Alkoxy refers to a radical -OR where R represents an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.
  • Alkoxycarbonyl refers to a radical -C(O)-alkoxy where alkoxy is as defined herein.
  • Alkylarylamino refers to a radical -NRR' where R represents an alkyl or cycloalkyl group and R' is an aryl as defined herein
  • Alkylsulfonyl refers to a radical -S(O) 2 R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl and the like.
  • Alkylsulfinyl refers to a radical -S(O)R where R is an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfmyl and the like.
  • Alkylthio refers to a radical -SR where R is an alkyl or cycloalkyl group as defined herein that may be optionally substituted as defined herein. Representative examples include, but are not limited to methylthio, ethylthio, propylthio, butylthio, and the like.
  • Amino refers to the radical -NH .
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as- indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene,
  • Arylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl group.
  • Typical arylalkyl groups include, but are not limited to, benzyl, 2- phenylethan-1-yl, 2-phenylethen-l-yl, naphthylmethyl, 2-naphthylethan-l-yl, 2- naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like.
  • arylalkanyl arylalkenyl and/or arylalkynyl
  • an arylalkyl group is (C 6 -C 0 ) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C ⁇ -C 10 ) and the aryl moiety is (C 6 -C 20 ).
  • Arylalkyloxy refers to an -O-arylalkyl radical where arylalkyl is as defined herein.
  • Arylamino means a radical -NHR where R represents an aryl group as defined herein.
  • Aryloxycarbonyl refers to a radical -C(O)-O-aryl where aryl is as defined herein.
  • Carbamoyl refers to the radical -C(O)N(R) 2 where each R group is independently hydrogen, alkyl, cycloalkyl or aryl as defined herein, which may be optionally substituted as defined herein.
  • Carboxy means the radical -C(O)OH.
  • Cyano means the radical -CN.
  • Cycloalkyl refers to a saturated or unsaturated cyclic alkyl group. Where a specific level of saturation is intended, the nomenclature “cycloalkanyl” or “cycloalkenyl” is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. In a preferred embodiment, the cycloalkyl group is (C -C ⁇ 0 ) cycloalkyl, more preferably (C 3 -C 6 ) cycloalkyl.
  • Cycloheteroalkyl refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are independently replaced with the same or different heteroatom.
  • Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.
  • Typical cycloheteroalkyl groups include, but are not limited to, groups derived from dioxanes, dioxolanes, epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, tetrahydrofuran, tetrahydropyran and the like.
  • Cvcloheteroalkyloxycarbonyl refers to a radical -C(O)-OR where R is cycloheteroalkyl is as defined herein.
  • Dialkylamino means a radical -NRR' where R and R' independently represent an alkyl or cycloalkyl group as defined herein. Representative examples include, but are not limited to dimethylamino, methyl ethylamino, di-(l- methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyciohexyl)(propyl)amino, and the like.
  • Halo means fluoro, chloro, bromo, or iodo.
  • Haloalkyl means an alkyl radical substituted by one or more halo atoms wherein alkyl and halo is as defined herein.
  • Heteroalkyloxy means an -O-heteroalkyl group where heteroalkyl is as defined herein.
  • Heteroalkyl, Heteroalkanyl, Heteroalkenyl, Heteroalkynyl refer to alkyl, alkanyl, alkenyl and alkynyl groups, respectively, in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyrid
  • the heteroaryl group is between 5-20 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Heteroaryloxy refers to an -O-heteroarylalkyl radical where heteroarylalkyl is as defined herein.
  • Heteroaryloxycarbonyl refers to a radical -C(O)-OR where R is heteroaryl as defined herein.
  • Heteroarylalkyl refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp 3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylalkenyl and/or heterorylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is 1-10 membered and the heteroaryl moiety is a 5-20 membered heteroaryl.
  • Haldroxy refers to the radical -OH.
  • Leaving group has the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group capable of being displaced by a nucleophile and includes halo (such as chloro, bromo, and iodo), alkoxycarbonyl (e.g., acetoxy), aryloxycarbonyl, mesyloxy, tosyloxy, trifluoromethanesulfonyloxy, aryloxy (e.g, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamino, and the like.
  • halo such as chloro, bromo, and iodo
  • alkoxycarbonyl e.g., acetoxy
  • aryloxycarbonyl mesyloxy, tosyloxy, trifluoromethanesulfonyloxy
  • aryloxy e.g, 2,4-dinitrophenoxy
  • methoxy N,O-d
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the
  • “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzen
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Patient includes humans.
  • human and “patient” are used interchangeably herein.
  • Preventing or “prevention” refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a patient that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Prodrug refers to a pharmacologically inactive derivative of a drug molecule that requires a transformation within the body to release the active drug.
  • prodrugs are designed to overcome pharmaceutical and/or pharmacokinetically based problems associated with the parent drug molecule that would otherwise limit the clinical usefulness of the drug.
  • Promoiety refers to a form of protecting group that when used to mask a functional group within a drug molecule converts the drug into a prodrug.
  • the promoiety will be attached to the drug via bond(s) that are cleaved by enzymatic or non-enzymatic means in vivo. Ideally, the promoiety is rapidly cleared from the body upon cleavage from the prodrug.
  • Protecting group refers to a grouping of atoms that when attached to a reactive group in a molecule masks, reduces or prevents that reactivity. Examples of protecting groups can be found in Green et al, "Protective Groups in Organic
  • amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ”), tert-butoxycarbonyl ("Boc”), trimethylsilyl ("TMS”), 2-trimethylsilyl-ethanesulfonyl (“SES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro- veratryloxycarbonyl (“NVOC”) and the like.
  • hydroxy protecting groups include, but are not limited to, those where the hydroxy group is either acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • Sulfonylamino refers to a radical -NR'S(O 2 )R, where R' and R are each independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, as defined herein.
  • “Therapeutically effective amount” means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to effect such treatment for the disease.
  • the “therapeutically effective amount” will vary depending on the compound, the disease and its severity and the age, weight, etc., of the patient to be treated.
  • Thiocyanato refers to the radical -SCN.
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the patient. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discemible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • the present invention provides a method of modulating an LPA2 or Edg-4 receptor (e.g., human Edg-4, GenBank Accession Nos. AF233092 or AFOl 1466) mediated biological activity.
  • a cell expressing the Edg-4 receptor is contacted with an amount of an Edg-4 receptor agonist or antagonist sufficient to modulate the Edg-4 receptor mediated biological activity.
  • Edg-4 is a G protein coupled receptor ("GPCR").
  • the Edg-4 (LPA2) receptor is encoded by an endothelial differentiation gene and along with related receptors, Edg-2 (LPAl) and Edg-7 (LPA3), binds lysophosphatidic acid (“LPA").
  • LPA G protein coupled receptor
  • the Edg-4 receptor is a human receptor.
  • the Edg-4 receptor may be expressed by recombinant DNA methods well known to those of skill in the art.
  • Particularly useful cell types for expressing and assaying Edg-4 include, but are not limited to, HTC4 (rat hepatoma cells), RH7777 (rat hepatoma cells), HepG2 (human hepatoma cells), CHO (Chinese hamster ovary cells) and HEK-293 (human embryonic kidney cells).
  • Particularly useful vectors for expressing G-protein receptors include, but are not limited to, pLXSN and pCMV (Clontech Labs, Palo Alto, CA; Invitrogen Corporation, Carlsbad, CA).
  • DNA encoding Edg-4 is well known (e.g, human Edg-4, GenBank Accession Nos. AF233092 or AFOl 1466) and can be transfected into human or mammalian cells according to methods known to those of skill in the art.
  • DNA encoding human Edg-4 can be co-transfected with a standard packaging vector, such as those described above, which provides an ecotropic envelope for viral replication, into a packaging cell line such as GP-293 (Clontech Labs, Palo Alto, CA).
  • GP-293 Cell Line
  • DNA encoding Edg-4 can be transfected into the EcoPack-293 cell line which has, in addition to gag and pol, the ewv gene to produce an ecotropic envelope.
  • Both methods i.e., co-transfection with a packaging vector or use of EcoPack-293 enable the production of an ecotropic envelope for viral packaging, and can thus advantageously be used to transfect rat and mouse cells.
  • AmphoPack-293 cell line can be used (Clontech Labs, Palo Alto, CA).
  • Edg-4 receptors include, but are not limited to, CaOV-3 human ovarian cancer cells, MDA-MB- 453 and MDA-MB-231 breast cancer cells, HT-1080 human fibrosarcoma, HUVEC cells and OV202 human ovarian cancer cells (ATCC, Manassas, VA; Vec
  • cells which express the Edg-4 receptor may grown in vitro or may be part of a complex organism such as, for example, a mammal. It is contemplated that the methods of the current invention will be applicable to modulation of Edg-4 receptor activity, regardless of the local environment.
  • cells that express the Edg-4 receptor are grown in vitro (i.e., are cultured).
  • cells that express the Edg-4 receptor are in vivo (i.e., are part of a complex organism).
  • the cells, in which the method of the invention may be practiced include, but are not limited to, hepatoma cells, ovarian cells, epithelial cells, fibroblast cells, neuronal cells, cardiac myocytes, endothelial cells, carcinoma cells, pheochromocytoma cells, myoblast cells, platelet cells and fibrosarcoma cells. More specifically, the cells in which the invention may be practiced include, but are not limited to, 0V202 human ovarian cells, HTC rat hepatoma cells, CAOV-3 human ovarian cancer cells, MDA-MB-453 breast cancer cells, MDA-MB-231 breast cancer cells, HUVEC, A431 human epitheloid carcinoma cells and HT-1080 human fibrosarcoma cells.
  • an Edg-4 receptor mediated biological activity is modulated in a subject or in an animal model.
  • a therapeutically effective amount of a modulator of the Edg-4 receptor is administered to the subject or an animal.
  • the subject or animal is in need of such treatment.
  • the biological activity mediated by the Edg-4 receptor may include, for example, calcium mobilization, VEGF synthesis, IL-8 synthesis, platelet activation, cell migration, phosphoinositide hydrolysis, inhibition of cAMP formation or actin polymerization.
  • the biological activity mediated by the Edg-4 receptor includes, but is not limited to, apoptosis, angiogenesis, inhibition of wound healing, inflammation, cancer invasiveness or atherogenesis.
  • the biological activity mediated by the Edg-4 receptor is cell proliferation, which may lead to ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colon cancer or prostrate cancer. In one embodiment, cell proliferation is stimulated by LPA.
  • the biological activity mediated by the Edg-4 receptor may include increasing fatty acids levels (e.g., free fatty acids and lyso- phosphatidylcholine) which may lead to acute lung diseases, such as adult respiratory distress syndrome ("ARDS”) and acute inflammatory exacerbation of chronic lung diseases like asthma.
  • ARDS adult respiratory distress syndrome
  • chronic lung diseases like asthma.
  • compounds that block Edg-4 can be potentially effective immunosuppressive agents because activated T cells have Edg-4 receptors (Zheng et al, 2000, FASEB J 14:2387-2389).
  • Edg-4 antagonists may be useful in a variety of autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephrosis, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia. Additionally, Edg-4 antagonists can be used in organ transplantation.
  • the modulator exhibits selectivity for the Edg-4 receptor.
  • the modulator exhibits at least about 5 to about 200 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • Inhibitory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.25 (Example 25), 6.27 (Example 27) and 6.28 (Example 28) respectively.
  • inhibitory selectivity can be measured by a calcium mobilization assay.
  • Other assays suitable for determining inhibitory selectivity would be known to one of skill in the art.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to other non-Edg receptors, including, but not limited to, other GPCRs, ion channels, growth factor receptors and the like.
  • the modulator exhibits at least about 63 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 30 fold inhibitory selectivity for Edg-4 relative to other Edg receptors. In still another embodiment, the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 5 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 63 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 30 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors. In still another embodiment, the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 5 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator of cell proliferation exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 10 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors. In still another embodiment, the modulator of cell proliferation exhibits at least about 200 fold inhibitory selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits activating selectivity for the Edg-4 receptor.
  • the modulator exhibits at least about 5 to about 200 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • Activating selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.13 (Example 13), 6.15 (Example 15) and 6.16 (Example 16) respectively.
  • activating selectivity can be measured by a calcium mobilization assay.
  • Other assays suitable for determining activating selectivity would be known to one of skill in the art.
  • the modulator exhibits at least about 200 fold activating selectivity for Edg-4 relative to other non-Edg receptors, including, but not limited to, other GPCRs, ion channels, growth factor receptors and the like. In another embodiment, the modulator exhibits at least about 63 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 30 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 10 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the agonist modulator exhibits at least about 5 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors. In yet another embodiment, the modulator exhibits at least about 63 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 30 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 10 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator exhibits at least about 5 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • of cell proliferation exhibits at least about 200 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 10 fold activating selectivity for Edg-4 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 10 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the modulator of cell proliferation exhibits at least about 200 fold activating selectivity for Edg-4 relative to Edg-2 and Edg-7 receptors.
  • the Edg-4 modulator is not a lipid.
  • the modulator of Edg-4 receptor mediated biological activity does not contain a phosphate group such as a phosphoric acid, a cyclic phosphate ester or a linear phosphate ester.
  • the modulator of the Edg-4 receptor is not a phospholipid.
  • phospholipid includes all phosphate (both phosphate esters and phosphoric acids) containing glycerol derivatives with an alkyl chain of greater 10 carbon atoms or greater, any N-acyl ethanolamide phosphate derivative (both phosphate esters and phosphoric acids), LPA, SIP or any of their analogues (both phosphate esters and phosphoric acids) (see, e.g., Bandoh, et al, 2000, FEBS Lett. 428, 759; Bittman et al, 1996, J.
  • the modulator is also not a compound of structural formula:
  • X is O or S
  • R 20 is alkyl, substituted alkyl, aryl, substituted aryl or halo
  • R 2 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
  • R 2 is hydrogen, alkyl or substituted alkyl
  • R 24 is aryl, substituted aryl, heteroaryl or substituted heteroaryl; or alternatively R 23 and R 24 form a cycloalkyl ring (International Application No: WO 01/60819).
  • the modulator is not any compound of the formula below:
  • R 2 o, R 2 ⁇ and R 24 are as previously defined.
  • the modulator is not any compound disclosed in International Application No: WO
  • the Edg-4 modulator may be a biomolecule such as a nucleic acid, protein,
  • the Edg-4 modulator may be oligomers or monomers of the above biomolecules such as amino acids, peptides, monosaccharides, disaccharides, nucleic acid monomers, dimers, etc., or any combination thereof.
  • the Edg-4 modulator may also be a synthetic polymer or any combination of synthetic polymer with biomolecules including monomers or oligomers of biomolecules.
  • the Edg-4 modulator may also be an organic molecule of molecular weight less than 750 daltons. In one embodiment, the molecular weight is about 200 to about
  • the molecular weight is about 200 to about 750 daltons. In yet another embodiment, the molecular weight is about 200 to about 500 daltons. Preferably, the molecular weight is about 300 to about 500 daltons.
  • the modulator may, for example, facilitate inhibition of the Edg-4 receptor through direct binding to the LPA binding site of the receptor, binding at some other site of the Edg-4 receptor, interference with Edg-4 or LPA biosynthesis, covalent modification of either LPA or the Edg-4 receptor, or may otherwise interfere with Edg-4 mediated signal transduction.
  • the agonist or antagonist binds to the Edg-4 receptor with a binding constant between about 10 ⁇ M and about 1 fM. In another embodiment, the modulator binds to the Edg-4 receptor with a binding constant between about 10 ⁇ M and about 1 nM. In another embodiment, the modulator binds to the Edg-4 receptor with a binding constant between about 1 ⁇ M and about 1 nM. In another embodiment, the modulator binds to the Edg-4 receptor with a binding constant between about 100 nM and about 1 nM. In another embodiment, the modulator binds to the Edg-4 receptor with a binding constant between about 10 nM and about 1 nM. Preferably, the modulator binds to the Edg-4 receptor with a binding constant better (i.e., less) than about 10 nM.
  • the modulator is a compound of structural formula (I):
  • Ri is hydrogen, alkyl, substituted alkyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkylarylamino, substituted alkylarylamino, amino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylamino, substituted arylamino, arylalkyl, substituted arylalkyl, dialkylamino, substituted dialkylamino, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl sulfonylamino or substituted sulfonylamino;
  • A is NR 2 , O or 5;
  • R 2 is hydrogen, alkyl or substituted alkyl
  • B and C are independently alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl.
  • R is alkyl, substituted alkyl, substituted aryl, substituted aryl, arylalkyloxy or substituted sulfonylamino. More preferably, R ⁇ is substituted alkyl. Even more preferably, Ri is substituted haloalkyl. Most preferably, Ri is substituted trifluoroalkyl (preferably, trifluoroalkanyl).
  • Ri has the structural formula (II):
  • R is haloalkyl or substituted haloalkyl
  • R 4 is oxo or thiono; and R 5 and R ⁇ are independently hydrogen, halo, alkyl or substituted alkyl.
  • R 3 is fluoroalkyl
  • R 4 is oxo and R 5 and R are independently hydrogen, halo or alkyl. More preferably, R is trifluoromethyl, R 4 is oxo and R 5 and R ⁇ 5 are independently hydrogen, chloro or methyl.
  • R 5 and Re are hydrogen. In another preferred embodiment, R 5 is hydrogen and R is chloro or methyl.
  • X is O
  • A is NR 2 and R 2 is hydrogen.
  • B and C are alkyl, substituted alkyl, independently, aryl, substituted aryl, heteroaryl or substituted heteroaryl. More preferably, B and C are independently indolo, substituted indolo, imidazolo, substituted, imidazolo, pyrazolo, substituted pyrazolo, phenyl or substituted phenyl. Even more preferably, B is heteroaryl or substituted heteroaryl and C is aryl or substituted aryl. Most preferably, B is pyrazolo or substituted pyrazolo and C is phenyl or substituted phenyl.
  • the modulator is a compound of structural formula (III):
  • R 7 is hydrogen, alkyl, substituted alkyl or halo
  • R 8 is hydrogen, carbamoyl or substituted carbamoyl
  • R 9 , Rio and Rn are independently hydrogen, alkoxy, substituted alkoxy, halo or optionally, R 9 and Rio together with the carbons to which they are attached form a [1,3] dioxolane ring.
  • Preferred modulators include compounds of the structural formula shown below:
  • the agonists or antagonists that can be utilized as part of the methods of the present invention are compounds of structural formula (IV):
  • each of R,, R 2 , R 3 , R 4 or R 5 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 ,
  • each R 5 and Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • C ⁇ o)alkyl -CO 2 (C ⁇ -C, 0 )alkyl, -(d-C, 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cyclo alkyl, -(C 8 -C] )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl,
  • X and Y are each independently C or N;
  • Z is O, S, C or N, wherein if Z is O or S, then R 3 is an electron pair;
  • Ri and R 2 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 2 and R 3 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 4 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • Another embodiment of the present invention is directed to compounds of structural formula (V), which can be utilized for the purpose of this invention:
  • each of Ri, R 2 , R , R-jor R 5 is independently -H, -halo, -NO 2 , -CN, -OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C ⁇ 0 )alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl,
  • each Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C,-C ⁇ o)alkyl, -C(O)(d-C,o)alkyl, -C(O)NH(CH 2 ) m (C ⁇ -C ⁇ o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((d-C,o)alkyl(d- C,o)alkyl), -CO 2 (C ⁇ -C ⁇ o)alkyl, -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C
  • Ri and R or R 2 and R 3 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • R ⁇ and R 2 are independently aryl, substituted aryl, heteroaryl or substituted heteroaryl.
  • R 2 is indole, and R 3 and R 4 are hydrogen.
  • the modulator is a compound of structural formula (VI):
  • each of R], R 2 , R 3 , R or R 5 is independently -H, -halo, -NO 2 , -CN, -OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -
  • Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C,o)alkyl(CrC,o)alkyl, -O(d-C 10 )alkyl, -C(O)(C,-C, 0 )alkyl,
  • X, Y and Z are independently O, S, C or N, wherein if X, Y or Z is O or S, Ri is an electron pair;
  • Ri and R 2 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 3 and Rj can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring; Ri and R can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring; and
  • R and R 5 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • Ri and R 2 together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring. In a more specific embodiment,
  • Ri and R 4 together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • Illustrative modulators of the invention include, but are not limited to, the following compound:
  • the modulator is a compound of structural formula (VII):
  • each of R ⁇ , R 2 , R 3 , Rt , R 5 , R 7 or R 8 is independently -H, -halo, - ⁇ O 2 , -CN, -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bic
  • each R 5 or Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (C,-Ci 0 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C 1 -C 10 )alkyl(C 1 - C ⁇ o)alkyl), -CO 2 (C 1 -C, 0 )alkyl, -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl
  • X is O, S, C or N, wherein if X is O or S, Ri is an electron pair;
  • Y and Z are independently N or C, wherein if Y or Z is N, Ri and R 2 are each an electron pair.
  • Illustrative modulators of the invention include:
  • the modulator is a compound of structural formula (VIII):
  • each of Ri, R 2 , R 3 , R 4 , R 5 , R , R 8 , R 9 or Rio is independently -H, -halo, -NO 2 , -CN, -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -
  • each R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • C,o)alkyl -CO 2 (C ⁇ -C 10 )alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl,
  • X and Y are independently O, S or N, wherein if X or Y is O or S, R 9 and Rio are an electron pair.
  • R 7 is a substituted or unsubstituted aryl.
  • Egd-4 modulators includes:
  • the modulator is a compound of structural formula
  • each of Ri, R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , R 9 or Rio is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C, 0 )alkyl, -(C 2 - C 10 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicy
  • each Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C,o)alkyl(d-C ⁇ o)alkyl, -O(C,-C 10 )alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl,
  • C ⁇ o)alkyl or -SO 2 NH 2 ;
  • m is independently an integer ranging from 0 to 8; and
  • p is independently an integer ranging from 0 to 5.
  • R 2 is a substituted alkyl, and one or more of R 5 , R 7 , R 8 , R 9 and R]o are halos.
  • R 2 is a halo-substituted alkyl.
  • R 2 is CF .
  • Specific examples of the modulators include:
  • the modulator is a compound of structural formula (X):
  • each of Ri, R 2 , R 3 , R 4 , R 5 or R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C C ⁇ 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)
  • each R 5 or Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • Ci 0 alkyl, or -SO 2 NH 2 ;
  • m is independently an integer ranging from 0 to 8;
  • p is independently an integer ranging from 0 to 5;
  • Ri and R 2 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 3 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 3 and R 4 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 7 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • R 3 and R 7 are substituted or unsubstituted aryls.
  • An illustrative modulator of the invention includes:
  • the modulator is a compound of structural formula (XI):
  • each of Ri, R 2 , R 3 , * , R 5 , R 7 or R 8 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 ,
  • each R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C,o)a ⁇ kyl(C,-C,o)alkyl, -O(C,-C 10 )alkyl, -C(O)(C,-C ⁇ 0 )alkyl,
  • C 10 )alkyl ), -CO 2 (C ⁇ -C 10 )alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl,
  • C 10 )alkyl or -SO 2 NH 2 ;
  • m is independently an integer ranging from 0 to 8;
  • p is independently an integer ranging from 0 to 5;
  • Ri and R 2 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 2 and R 3 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 3 and t can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R and R 7 can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R 7 and Rs can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring;
  • R ⁇ and Rs can optionally together form a 5-, 6- or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • R 2 and R 3 together form a 5-membered ring.
  • Illustrative examples of the modulators of the invention include:
  • Another illustrative compound of the invention has the following structure:
  • the modulator is a compound of structural formula (XII):
  • each of Ri, R 2 , R 3 , R 4 , R 5 or R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -(CH 2 ) m N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -C(OH)R 5 , -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C l0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C M
  • each R 5 or Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • m is independently an integer ranging from 0 to 8;
  • p is independently an integer ranging from 0 to 5;
  • R 3 or can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring.
  • R ⁇ or R 2 can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring;
  • R 2 or R can optionally form a substituted or unsubstituted cyclic, aromatic, heterocyclic, heteroaryl or cycloheteroalkyl ring.
  • modulators of the invention include:
  • the compounds depicted in Scheme 1 are compounds of structural formula (I).
  • compounds of structural formula (I) may be made by the route depicted in Scheme 1.
  • Condensation of commercially available thiosemicarbazide 1 with acetophenone 3 in the presence of acid, (e.g., acetic acid) provides thiosemicarbazone 5.
  • acid e.g., acetic acid
  • strong base e.g., lithium diisopropylamide
  • the compounds depicted in Scheme 2 are compounds of structural formula (IX).
  • compounds of structural formula (IX) may be made by the route depicted in Scheme 2.
  • Unsubstituted or substituted pyridyl hydrazine 2 is reacted with unsubstituted or substituted benzoic acid 1 in the presence of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HC1), 4- methylmorpholine and 1-hydroxybenzotriazole hydrate (HOBt), in anhydrous 1 :1 dichloromethane/acetonitrile.
  • Phosphorous oxychloride is then added to the solution of resulting compound 3 in toluene, and the compound of formula (IX) 4 is obtained.
  • Illustrative compounds 145, 147, 149, 151, 153, 155, 157 and 159 are commercially available from Specs (http//:www.specsnet.com); compounds 163, 165 and 167 are available from Chemdiv (http//www.chemdiv.com); compound 161 is available from Tripos (http://www.tripos.com); and compound 169 is available for purchase from Comgenex (http://www.comgenex.com).
  • the present invention provides a method of modulating an LPA3 or Edg-7 receptor (e.g. human Edg-7, GenBank Accession No. AF127138) mediated biological activity.
  • a cell expressing the Edg-7 receptor is contacted with an amount of an Edg- 7 receptor agonist or antagonist sufficient to modulate the Edg-7 receptor mediated biological activity.
  • the agonists or antagonists can be utilized in the methods of the present invention and are compounds of structural formula (XIII):
  • X is NR 3 , S or O
  • R] is hydrogen, alkyl, substituted alkyl, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, amino, carbamoyl, substituted carbamoyl, oxo, thiono or -NR 4 ;
  • R 2 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkyloxy, substituted alkyloxy, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, amino, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted
  • heteroaryloxy substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl or R is hydrogen, alkyl, substituted alkyl, alkylthio, substituted alkylthio, alkylsulfonyl, substituted alkylsulfonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylsulfonyl, substituted arylsulfonyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl or substituted heteroalkyl;
  • R 4 is alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl substituted heteroaryl, cycloheteroalkyl, substituted cycloheteroalkyl, and
  • R 5 and R ⁇ s are independently hydrogen, alkyl, substituted alkyl, acylamino, substituted acylamino, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, alkylsulfonyl, substituted alkylsulfonyl, alkylsulfinyl, substituted alkylsulfinyl, arylalkyloxy, substituted arylalkyloxy, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryloxy, substituted heteroaryloxy, heteroaryl, substituted heteroaryl, heteroalkyl, substituted heteroalkyl or optionally along with the carbon to which they are attached form an aryl, substituted aryl, cycloalky
  • the modulator is a compound of structural formula:
  • Ri is oxo, thiono or NJL t , more preferably, Rj is oxo or R t .
  • R 4 is acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl or substituted carbamoyl.
  • t is substituted carbamoyl..
  • R 2 is acyl, substituted acyl, acylamino, substituted acylamino, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, alkylsulfonyl, substituted alkylsulfonyl, aryloxycarbonyl, substituted aryloxycarbonyl, carbamoyl, substituted carbamoyl, or
  • R 2 is substituted alkoxycarbonyl or
  • R 5 and R 6 along with the carbon to which they are attached form a cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl ring. More preferably, R 5 and Re along with the carbon to which they are attached form a substituted cycloheteroalkyl ring.
  • the agonists or antagonists are also compounds of structural formula (XIV):
  • each of Ri, R 2 , R 3 ⁇ and R is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C 10 )alkyl, -(C 2 -C l0 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -Cj 4 )bicycloalkyl, -(C 5 -C ⁇ o)cyclo
  • each R 5 and R is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)alkyl(C,-C ⁇ 0 )alkyl, -O(C,-C ⁇ o)alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (d-C 10 )alkyl, -OCF 3 , -benzyl, -C0 2 (CH 2 ) m CH((Ci-Cio)alkyl(Ci- C ⁇ o)alkyl), -CO 2 (C ⁇ -C 10 )alkyl, -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl
  • Ri, R 2 , R 3 R and R taken in any combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6- membered aromatic ring; Ri , R 2 , R 3 R and R 7 can also be an electron such that when two groups are on adjacent carbon atoms they form a double bond; two R ⁇ groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the modulator is a compound of structural formula (XV):
  • each of Ri, R 2 , R 3 R 4 and R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C ⁇ o)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkeny
  • each R 5 and R is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)aIkyl(C ⁇ -C ⁇ o)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (d-C 10 )alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C 1 -C 10 )alkyl(d- C ⁇ o)alkyl), -C0 2 (C ⁇ -C ⁇ o)alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(
  • X is C, or N
  • Ri, R 2 , R R 4 and R 7 taken in any combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6- membered aromatic ring;
  • Ri, R , R 3 R 4 and R 7 can also be an electron such that when two groups are on adjacent carbon atoms they form a double bond; two R groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the compound is of formula:
  • the modulator is of structural formula (XVI):
  • each of Ri, R 2 , R 3 R 4 and R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-Co)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C ⁇ o)alkyl(C ⁇ -C,o)alkyl, -O(d-d 0 )alkyl, -C(O)(C,-C, 0 )alkyl, -C(O) H(CH 2 ) m (C,-C ⁇ o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((d-do)alkyl(d- C ⁇ o)alkyl), -CO 2 (C,-C ⁇ 0 )alkyl, -(C ⁇ -C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C, 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl,
  • the a modulator is of structural formula (XVII):
  • each of Ri, R 2> R 3 R 4 and R 7 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C] 4 )bicycloalkyl, -(C 5 -C !
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C,o)alkyl(C 1 -C 1 o)alkyl, -O(C,-C,o)alkyl, -C(O)(d-C 10 )alkyl, -C(O)NH(CH 2 ) m (C,-C,o)alkyl, -OCF 3 , -benzyl, C 10 )alkyl), -CO 2 (d-C 10 )alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C 1 o)cyclo
  • the modulator is of formula:
  • Edg-7 receptor is a G protein coupled receptor ("GPCR").
  • GPCR G protein coupled receptor
  • the Edg-7 (LPA3) receptor is encoded by an endothelial differentiation gene and along with related receptors, Edg-2 (LPAl) and Edg-4 (LPA2), binds lysophosphatidic acid (“LPA”).
  • LPA lysophosphatidic acid
  • the Edg-7 receptor is a human receptor.
  • the Edg-7 receptor may be expressed by recombinant DNA methods well known to those of skill in the art.
  • Particularly useful cell types for expressing and assaying Edg-7 include, but are not limited to, HTC4 (rat hepatoma cells), RH7777 (rat hepatoma cells), HepG2 (human hepatoma cells), CHO (Chinese hamster ovary cells) and HEK-293 (human embryonic kidney cells).
  • Particularly useful vectors for expressing G-protein receptors include, but are not limited to, pLXSN and pCMV (Clontech Labs, Palo Alto, CA; Invitrogen Corporation, Carlsbad, CA).
  • DNA encoding Edg-7 (human Edg-7, GenBank accession AFOl 1466) can be transfected into human or mammalian cells according to methods known to those of skill in the art.
  • DNA encoding human Edg-7 can be co-transfected with a standard packaging vector, such as those described above, which provides an ecotropic envelope for viral replication, into a packaging cell line such as GP-293 (Clontech Labs, Palo Alto, CA).
  • DNA encoding Edg-7 can be transfected into the EcoPack-293 cell line which has, in addition to gag and pol, the env gene to produce an ecotropic envelope.
  • Both methods i.e., co-transfection with a packaging vector or use of EcoPack-293
  • AmphoPack-293 cell line can be used (Clontech Labs, Palo Alto, CA).
  • Edg-7 receptors include, but are not limited to, CaOV-3 human ovarian cancer cells, MDA-MB- 453 and MDA-MB-231 breast cancer cells, HT-1080 human fibrosarcoma, HUVEC cells and OV202 human ovarian cancer cells (ATCC, Manassas, VA; Vec Technologies Inc. (Rensselaer, NY); Dr. Edward Goetzl, University of California, San Francisco, San Francisco, CA).
  • cells which express the Edg-7 receptor may grown in vitro or may be part of a complex organism such as, for example, a mammal. It is contemplated that the methods of the current invention will be applicable to modulation of Edg-7 receptor activity, regardless of the local environment.
  • cells that express the Edg-7 receptor are grown in vitro (i.e., are cultured).
  • cells that express the Edg-7 receptor are in vivo (i.e., are part of a complex organism).
  • the cells in which the method of the invention may be practiced include, but are not limited to, hepatoma cells, ovarian cells, epithelial cells, fibroblast cells, neuronal cells, cardiac myocytes, carcinoma cells, pheochromocytoma cells, myoblast cells, endothelial cells, platelet cells and fibrosarcoma cells. More specifically, the cells in which the invention may be practiced include, but are not limited to, OV202 human ovarian cells, hepatoma cells (e.g.
  • HTC, Rh7777, HepG2 SKOV3 human ovarian cancer cells, CAOV-3 human ovarian cancer cells, HEY human ovarian cancer cells, HTC rat hepatoma cells, CAOV-3 human ovarian cancer cells, MDA- MB-453 breast cancer cells, MDA-MB-231 breast cancer cells, A431 human epitheloid carcinoma cells and HT-1080 human fibrosarcoma cells.
  • an Edg-7 receptor mediated biological activity is modulated in a subject or in an animal model.
  • a therapeutically effective amount of an modulator of the Edg-7 receptor is administered to the subject or animal.
  • the subject or an animal is in need of such treatment.
  • the biological activity mediated by the Edg-7 receptor may include, for example, calcium mobilization, VEGF synthesis, IL-8 synthesis, platelet activation, cell migration, phosphoinositide hydrolysis, inhibition of cAMP formation or actin polymerization.
  • the biological activity mediated by the Edg-7 receptor also includes, but is not limited to, apoptosis, angiogenesis, inhibition of wound healing, inflammation, cancer invasiveness or atherogenesis.
  • the biological activity mediated by the Edg-7 receptor is cell proliferation, which may lead to ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer or prostrate cancer.
  • cell proliferation is stimulated by LPA.
  • the biological activity mediated by the Edg-7 receptor may include increasing fatty acids levels (e.g., free fatty acids and lyso- phosphatidylcholine) which may lead to acute lung diseases, such as adult respiratory distress syndrome ("ARDS”) and acute inflammatory exacerbation of chronic lung diseases like asthma.
  • ARDS adult respiratory distress syndrome
  • chronic lung diseases like asthma.
  • compounds that block Edg-7 can be potentially effective immunosuppressive agents because activated T cells have Edg-7 receptors (Zheng et al, 2000, FASEB J 14:2387-2389).
  • Edg-7 antagonists may be useful in a variety of autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephrosis, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia. Additionally, Edg-7 antagonists can be used in organ transplantation.
  • the modulator exhibits inhibitory selectivity for the Edg-7 receptor.
  • the modulator can exhibit at least about 200 fold inhibitory selectivity for Edg-7 relative to other Edg receptors.
  • Inhibitory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.4 (Example 4), 6.6 (Example 6) and 6.7 (Example 7) respectively.
  • Other assays suitable for determining inhibitory selectivity would be known to one of skill in the art.
  • Preferred assays include the calcium mobilization assay of Section 6.5.
  • the modulator exhibits at least about 100 fold inhibitory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator exhibits at least about 20 fold inhibitory selectivity for Edg-7 relative to other Edg receptors. In another embodiment, the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits at least about 100 fold inhibitory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits at least about 20 fold inhibitory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits at least about 10 fold inhibitory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors. In a preferred embodiment, an modulator of cell proliferation exhibits at least about 100 fold inhibitory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold inhibitory selectivity for Edg-7 relative to other Edg receptors. In still another embodiment, the modulator of cell proliferation exhibits at least about 10 fold inhibitory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits stimulatory selectivity for the Edg-7 receptor.
  • the modulator can exhibit at least about 200 fold stimulatory selectivity for Edg-7 relative to other Edg receptors.
  • Stimulatory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.5 (Example 5), 6.7 (Example 7) and 6.8 (Example 8) respectively.
  • Other assays suitable for determining stimulatory selectivity would be known to one of skill in the art.
  • Preferred assays include the calcium mobilization assay of Section 6.5.
  • the modulator exhibits at least about 100 fold stimulatory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator exhibits at least about 20 fold stimulatory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator exhibits at least about 10 fold stimulatory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold stimulatory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors. In still another embodiment, the modulator exhibits at least about 100 fold stimulatory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits at least about 20 fold stimulatory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the modulator exhibits at least about 10 fold stimulatory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • an modulator of cell proliferation exhibits at least about 100 fold stimulatory selectivity for Edg-7 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold stimulatory selectivity for Edg-7 relative to other Edg receptors. In still another embodiment, the modulator of cell proliferation exhibits at least about 10 fold stimulatory selectivity for Edg-7 relative to Edg-2 and Edg-4 receptors.
  • the Edg-7 modulator is not a lipid. In another embodiment, the Edg-7 modulator does not contain a phosphate group such as a phosphoric acid, a cyclic phosphate ester or a linear phosphate ester. In another embodiment, the Edg-7 modulator is not a phospholipid.
  • phospholipid includes all phosphate (both phosphate esters and phosphoric acids) containing glycerol derivatives with an alkyl chain of greater 10 carbon atoms or greater, any N- acyl ethanolamide phosphate derivative (both phosphate esters and phosphoric acids), LPA, SIP or any of their analogues (both phosphate esters and phosphoric acids) (see, e.g., Bandoh, et al, 2000, FEBS Lett. 428, 759; Bittman et al., 1996, J.
  • the Edg-7 modulator is not a compound of structural formula (XVIII):
  • X is O or S
  • R 2 o is alkyl, substituted alkyl, aryl, substituted aryl or halo
  • R 21 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
  • R 23 is hydrogen, alkyl or substituted alkyl
  • R 24 is aryl, substituted aryl, heteroaryl or substituted heteroaryl
  • R 2 and R 24 form a cycloalkyl ring (International Application No: WO 01/60819).
  • the modulator is not any compound of the formula below:
  • R 0 , R 2 ⁇ and R 24 are as previously defined.
  • the modulator is not any compound disclosed in International Application No: WO 01/60819.
  • the modulator is a agonist of the Edg-7 receptor.
  • the modulator can be a weaker agonist than the natural agonist and may compete with the natural agonist for the binding site.
  • the modulator is antagonist of the Edg-7 receptor.
  • the Edg-7 modulator may be a biomolecule such as a nucleic acid, protein, (i.e., an enzyme or an antibody) or oligosaccharide or any combination thereof.
  • the Edg-7 modulator may be oligomers or monomers of the above biomolecules such as amino acids, peptides, monosaccharides, disaccharides, nucleic acid monomers, dimers, etc., or any combination thereof.
  • the Edg-7 modulator may also be a synthetic polymer or any combination of synthetic polymer with biomolecules including monomers or oligomers of biomolecules.
  • the Edg-7 modulator may also be an organic molecule of molecular weight less than 750 daltons.
  • the molecular weight is about 200 to about 1000 daltons.
  • the molecular weight is about 200 to about 750 daltons.
  • the molecular weight is about 200 to about 500 daltons.
  • the molecular weight is about 300 to about 500 daltons.
  • the modulator may, for example, facilitate inhibition of the Edg-7 receptor through direct binding to the LPA binding site of the receptor, binding at some other site of the
  • the agonist or antagonist binds to the Edg-7 receptor with a binding constant between about 10 ⁇ M and about 1 fM.
  • the modulator binds to the Edg-7 receptor with a binding constant between about 10 ⁇ M and about 1 nM.
  • the modulator binds to the Edg-7 receptor with a binding constant between about 1 ⁇ M and about 1 nM.
  • the modulator binds to the Edg-7 receptor with a binding constant between about 100 nM and about 1 nM.
  • the modulator binds to the Edg-7 receptor with a binding constant between about 10 nM and about 1 nM.
  • the modulator binds to the Edg-7 receptor with a binding constant better (i.e., less) than about 10 nM.
  • the compounds of the invention may be obtained via the synthetic methods illustrated in Schemes 3 and 4.
  • Starting materials useful for preparing compounds of the invention and intermediates thereof are commercially available or can be prepared by well-known synthetic methods.
  • Other methods for synthesis of the compounds described herein are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (See e.g., Green et al, "Protective Groups in Organic Chemistry", (Wiley, 2 nd ed. 1991); Harrison et al, "Compendium of Synthetic Organic Methods", Vols.
  • analogues of 5 may be prepared simply by using different amines 1 and or isocyanates 3.
  • compounds other than the isocyanate 3 depicted may be reacted with amine 1 to provide compounds of the invention.
  • a wide variety of conventional synthetic methods may be used to synthesize compounds of structural Formula (I) other than those depicted above.
  • indolone 15 which may be alkylated, arylated, acylated or sulfonated by treatment with appropriate compounds to provide indolone 17.
  • acid and salt e.g., acetic acid and sodium acetate
  • indolone 15 which may be alkylated, arylated, acylated or sulfonated by treatment with appropriate compounds to provide indolone 17.
  • the alkylation, arylation, acylation or sulfontion can take place at either or both of the location indicated with a dashed bond.
  • analogues of 17 may be prepared simply by using different alkylation, arylation, acylation or sulfontion agents.
  • a wide variety of conventional synthetic methods may be used to synthesize compounds of structural Formula (I) other than those depicted above.
  • Illustrative compounds 709, 713, 715 and 723 are also commercially available from Specs (http//www.specs.net); illustrative compound 719 is commercially available from Asinex; illustrative compound 725 is commercially available from Tripos. Illustrative compounds 701, 711, and 719 are commercially available from Asinex. Illustrative compounds 717 is available from Labotest. Illustrative compound 727 is commercially available from Chemdiv. Illustrative compounds 729, 733, 735, and 737 are commercially available from Specs.
  • the present invention provides a method of modulating an LPAl or Edg-2 receptor (e.g., human Edg-2, GenBank Accession No., U78192) mediated biological activity.
  • a cell expressing the Edg-2 receptor is contacted with an amount of an Edg-2 receptor agonist or antagonist sufficient to modulate the Edg-2 receptor mediated biological activity.
  • the Edg-2 receptor is a G protein coupled receptor.
  • the Edg-2 (LPAl) receptor is encoded by an endothelial differentiation gene and along with related receptors, Edg-4 (LPA2) and Edg-7 (LPA3), binds lysophosphatidic acid ("LPA").
  • the Edg-2 receptor is a human receptor.
  • the Edg-2 receptor may be expressed by recombinant DNA methods well known to those of skill in the art.
  • Particularly useful cell types for expressing and assaying Edg-2 include, but are not limited to, HTC4 (rat hepatoma cells), RH7777 (rat hepatoma cells), HepG2 (human hepatoma cells), CHO (Chinese hamster ovary cells) and HEK-293 (human embryonic kidney cells).
  • Particularly useful vectors for expressing G-protein receptors include, but are not limited to, pLXSN and pCMV (Clontech Labs, Palo Alto, CA; Invitrogen Corporation, Carlsbad, CA).
  • DNA encoding Edg-2 is well known (e.g., human Edg-2, GenBank Accession No., U78192) and can be transfected into human or mammalian cells according to methods known to those of skill in the art.
  • DNA encoding human Edg- 2 can be co-transfected with a standard packaging vector, such as those described above, which provides an ecotropic envelope for viral replication, into a packaging cell line such as GP-293 (Clontech Labs, Palo Alto, CA).
  • DNA encoding Edg-2 can be transfected into the EcoPack-293 cell line which has, in addition to gag and pol, the env gene to produce an ecotropic envelope.
  • Both methods i.e. co-transfection with a packaging vector or use of EcoPack-293
  • AmphoPack-293 cell line can be used (Clontech Labs, Palo Alto, CA).
  • Edg-2 receptors include, but are not limited to, CaOV-3 human ovarian cancer cells, MDA-MB- 453 and MDA-MB-231 breast cancer cells, HT-1080 human fibrosarcoma, HUVEC cells and OV202 human ovarian cancer cells (ATCC, Manassas, VA; Vec Technologies Inc. (Rensselaer, NY); Dr. Edward Goetzl, University of California, San Francisco, San Francisco, CA).
  • cells which express the Edg-2 receptor may grown in vitro or may be part of a complex organism such as, for example, a mammal. It is contemplated that the methods of the current invention will be applicable to modulation of the Edg-2 receptor activity regardless of the local environment.
  • cells that express the Edg-2 receptor are grown in vitro (i.e., are cultured).
  • cells that express the Edg-2 receptor are in vivo (i.e., are part of a complex organism).
  • the cells, in which the method of the invention may be practiced include, but are not limited to, hepatoma cells, ovarian cells, epithelial cells, fibroblast cells, neuronal cells, cardiac myocytes, carcinoma cells, pheochromocytoma cells, myoblast cells, endothelial cells, platelet cells and fibrosarcoma cells. More specifically, the cells in which the invention may be practiced include, but are not limited to, OV202 human ovarian cell, HTC rat hepatoma cells, CAOV-3 and SKOV-3 human ovarian cancer cells, MDA-MB-453 breast cancer cells, MDA-MB-231 breast cancer cells, A431 human epitheloid carcinoma cells and HT-1080 human fibrosarcoma cells.
  • an Edg-2 receptor mediated biological activity is modulated in a subject or in an animal model.
  • a therapeutically effective amount of an modulator of the Edg-2 receptor is administered to the subject or an animal.
  • the subject or animal is in need of such treatment.
  • the biological activity mediated by the Edg-2 receptor may include, for example, calcium mobilization, VEGF synthesis, IL-8 synthesis, platelet activation, cell migration, phosphoinositide hydrolysis, inhibition of c AMP formation or actin polymerization.
  • the biological activity mediated by the Edg-2 receptor includes, but is not limited to, apoptosis, angiogenesis, inhibition of wound healing, inflammation, cancer invasiveness or atherogenesis.
  • the biological activity mediated by the Edg-2 receptor is cell proliferation, which may lead to ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colon cancer or prostrate cancer. In one embodiment, cell proliferation is stimulated by LPA.
  • the biological activity mediated by the Edg-2 receptor may include increasing fatty acids levels (e.g., free fatty acids and lyso- phosphatidylcholine) which may lead to acute lung diseases, such as adult respiratory distress syndrome ("ARDS”) and acute inflammatory exacerbation of chronic lung diseases like asthma.
  • ARDS adult respiratory distress syndrome
  • chronic lung diseases like asthma.
  • compounds that block Edg-2 can be potentially effective immunosuppressive agents because activated T cells have Edg-2 receptors (Zheng et al, 2000, FASEB J 14:2387-2389).
  • Edg-2 antagonists may be useful in a variety of autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephrosis, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia. Additionally, Edg-2 antagonists can be used in organ transplantation.
  • the modulator exhibits selectivity for the Edg-2 receptor.
  • the modulator exhibits at least about 5 to about 200 fold inhibitory selectivity for Edg-2 relative to other Edg receptors.
  • Inhibitory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.8 (Example 8), 6.10 (Example 10) and 6.11 (Example 11) respectively.
  • inhibitory selectivity can be measured by a calcium mobilization assay.
  • Other assays suitable for determining inhibitory selectivity would be known to one of skill in the art.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-2 relative to other non-Edg receptors, GPCRs, growth factor receptors, ion channels and the like.
  • the modulator exhibits at least about 40 fold inhibitory selectivity for Edg-2 relative to other Edg receptors.
  • the modulator exhibits at least about 12 fold inhibitory selectivity for Edg-2 relative to other Edg receptors. In another embodiment, the modulator exhibits at least about 5 fold inhibitory selectivity for Edg-2 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator exhibits at least about 40 fold inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator exhibits at least about 12 fold inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator exhibits at least about 5 inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • an modulator of cell proliferation exhibits at least about 200 fold inhibitory selectivity for Edg-2 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold inhibitory selectivity for Edg-2 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 200 fold inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold inhibitory selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors. In another embodiment, the modulator exhibits activating selectivity for the
  • the modulator exhibits at least about 5 to about 200 fold activating selectivity for Edg-2 relative to other Edg receptors.
  • Activating selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.8 (Example 8), 6.10 (Example 10) and 6.11 (Example 11) respectively.
  • activating selectivity can be measured by a calcium mobilization assay.
  • Other assays suitable for determimng activating selectivity would be known to one of skill in the art.
  • the modulator exhibits at least about 200 fold activating selectivity for Edg-2 relative to other non-Edg receptors, GPCRs, growth factor receptors, ion channels and the like.
  • the modulator exhibits at least about 40 fold activating selectivity for Edg-2 relative to other Edg receptors. In another embodiment, the modulator exhibits at least about 12 fold activating selectivity for Edg-2 relative to other Edg receptors.
  • the modulator exhibits at least about 5 fold activating selectivity for Edg-2 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator exhibits at least about 40 fold activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator exhibits at least about 12 fold activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors. In still another embodiment, the modulator exhibits at least about 5 activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • an modulator of cell proliferation exhibits at least about 200 fold activating selectivity for Edg-2 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold activating selectivity for Edg-2 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 200 fold activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold activating selectivity for Edg-2 relative to Edg-4 and Edg-7 receptors.
  • the Edg-2 modulator is not a lipid.
  • the modulator of Edg-2 modulator does not contain a phosphate group such as a phosphoric acid, a cyclic phosphate ester or a linear phosphate ester.
  • the Edg-2 modulator is not a phospholipid.
  • phospholipid includes all phosphate (both phosphate esters and phosphoric acids) containing glycerol derivatives with an alkyl chain of 10 carbon atoms or greater, dioctyl glycerol, any N-acyl ethanolamide phosphate derivative (both phosphate esters and phosphoric acids), LPA, SIP or any of their analogues (both phosphate esters and phosphoric acids) (see, e.g., Bandoh, et al, 2000, FEBS Lett. 428, 759; Bittman et al., 1996, J.
  • the Edg-2 modulator is not a compound of the formula:
  • X is O or S
  • R 2 o is alkyl, substituted alkyl, aryl, substituted aryl or halo
  • R 21 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
  • R 2 is hydrogen, alkyl or substituted alkyl
  • R 24 is aryl, substituted aryl, heteroaryl or substituted heteroaryl
  • R 23 and R 24 form a cycloalkyl ring (International Application No: WO 01/60819).
  • the modulator is not any compound of the formula below:
  • R 2 o, R 2 ⁇ and R 24 are as previously defined.
  • the modulator is not any compound disclosed in International Application No: WO 01/60819.
  • the Edg-2 modulator is an agonist of the Edg-2 receptor.
  • such an embodiment provides an Edg-2 modulator that is an agonist, but is a weaker agonist than a natural Edg-2 agonist (e.g., LPA) and as such, may compete with the natural agonist for Edg-2 binding site, resulting in a net inhibition of Edg-2 receptor activity.
  • a natural Edg-2 agonist e.g., LPA
  • the modulator is antagonist of the Edg-2 receptor.
  • the Edg-2 modulator may be a biomolecule such as a nucleic acid, protein (e.g., an enzyme, an antibody or a soluble Edg-2 receptor polypeptide) or oligosaccharide or any combination thereof.
  • the Edg-2 modulator may be oligomers or monomers of the above biomolecules such as amino acids, peptides, monosaccharides, disaccharides, nucleic acid monomers, dimers, etc., or any combination thereof.
  • the Edg-2 modulator may also be a synthetic polymer or any combination of synthetic polymer with biomolecules including monomers or oligomers of biomolecules.
  • the Edg-2 modulator may also be a small organic molecule.
  • a small organic molecule exhibits a molecular weight about 200 to about 1000 daltons, about 200 to about 750 daltons, 200 to about 500 daltons, or about 300 to about 500 daltons.
  • the small organic molecule can be orally administered to a subject.
  • the small organic molecule is capable of crossing the blood-brain barrier.
  • the modulator may, for example, facilitate inhibition of the Edg-2 receptor through direct binding to the LPA binding site of the receptor, binding at some other site of the Edg-2 receptor, interference with Edg-2 or LPA biosynthesis, covalent modification of either LPA or the Edg-2 receptor, or may otherwise interfere with Edg-2 mediated signal transduction.
  • the agonist or antagonist binds to the Edg-2 receptor with a binding constant between about 10 ⁇ M and 1 fM. In another embodiment, the agonist or antagonist binds to the Edg-2 receptor with a binding constant between about 10 ⁇ M and about 1 nM. In another embodiment, the agonist or antagonist binds to the Edg-2 receptor with a binding constant between about 1 ⁇ M and about 1 nM. In another embodiment, the agonist or antagonist binds to the Edg-2 receptor with a binding constant between about 100 nM and about 1 nM. In another embodiment, the agonist or antagonist binds to the Edg-2 receptor with a binding constant between about 10 nM and about 1 nM. Preferably, the agonist or antagonist binds to the Edg-2 receptor with a binding constant better (i.e., less) than about 10 nM.
  • the Edg-2 modulator has the structural formula (XX):
  • P, Q and R are independently aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl.
  • Q is cycloheteroalkyl, substituted cycloheteroalkyl and P and R are independently aryl or substituted aryl.
  • Q is cycloheteroalkyl or substituted cycloheteroalkyl and P and R are independently phenyl or substituted phenyl.
  • Q is heteroaryl or substituted heteroaryl and P and R are independently aryl or substituted aryl.
  • Q is heteroaryl or substituted heteroaryl and P and R are independently phenyl or substituted phenyl.
  • the Edg-2 modulator has the structural formula (XXI):
  • n 1, 2 or 3;
  • R ⁇ and R 2 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cyano, cyanato, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, oxo or thiono;
  • R 3 and R are independently hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, halo or thio;
  • B is NR 5 , O or S
  • R 5 is hydrogen, alkyl, substituted alkyl, alkylamino, substituted alkylamino, alkoxy, substituted alkoxy, amino, cyano, dialkylamino, substituted dialkylamino or hydroxy;
  • a and C are independently aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl or substituted heteroaryl.
  • Ri and R 2 are independently hydrogen, alkyl substituted alkyl, oxo or thiono. More preferably, Ri and R 2 are independently oxo or thiono.
  • R 3 and R are independently hydrogen or alkyl.
  • a and C are independently aryl, substituted aryl, heteroaryl or substituted heteroaryl. More preferably, A and C are aryl or substituted aryl. Most preferably, A and C are phenyl or substituted phenyl.
  • B is NR 5 and R 5 is hydrogen, alkyl or hydroxy.
  • n is 1
  • Ri and R 2 are oxo
  • R and R 4 are hydrogen
  • B is NR 5 and R 5 is hydroxy.
  • n is 1 , Ri and R 2 are oxo, R 3 and R t are hydrogen, B is NR 5 , R 5 is hydroxy, A and B are aryl or substituted aryl.
  • n is 1 , Ri and R 2 are oxo, R 3 and R 4 are hydrogen, B is NR 5 , R 5 is hydroxy, A and B are phenyl or substituted phenyl.
  • the Edg-2 modulators can also include the following compounds.
  • the modulator has the structural formula (XXII):
  • R 3 ⁇ is hydrogen, alkyl or substituted alkyl
  • R 32 is hydrogen, alkyl or substituted alkyl
  • R 3 is aryl, substituted aryl, heteroaryl or substituted heteroaryl
  • R 34 is aryl, substituted aryl, heteroaryl or substituted heteroaryl.
  • R 31 and R 2 are alkyl.
  • R 3 and R 3 are aryl or substituted aryl.
  • R 3 ⁇ and R 32 are alkyl and R 3 and R 34 are aryl or substituted aryl.
  • R 3 and R 34 are phenyl or substituted phenyl.
  • R 3 ⁇ and R 2 are methyl or ethyl and R 33 and R 4 are phenyl or substituted phenyl.
  • the Edg-2 modulator has the structural formula (XXIII):
  • each of R R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -d 0 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C
  • each R 5 and R ⁇ is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)alkyl(C 1 -C ⁇ o)alkyl, -O(C,-C ⁇ o)alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (C 1 -C,o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((d-C 10 )alkyl(d- C ⁇ o)alkyl), -CO 2 (d-C ⁇ 0 )alkyl, -(C,-C ⁇ 0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C -C ⁇ o)cycloalkyl, -(C
  • Ri and R 2 can optionally together form a 5-, 6-, or 7-membered substituted or unsubstituted cyclic or aromatic ring.
  • X and Y are both O.
  • Ri is -N(OH)aryl.
  • the Edg-2 modulator has the structural formula (XXIV):
  • each of Ri and R 2 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C ⁇ o)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C )
  • each of R 5 and Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C ⁇ -C ⁇ o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C,-C,o)alkyl, -C(O)NH(CH 2 ) m (d-do)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C 1 -C 10 )alkyl(d- C ⁇ o)alkyl), -CO 2 (d-C 10 )alkyl, -(d-C, 0 )alkyl, -(C 2 -C, 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C -C 10 )cycloalkyl, -(C 8 -C
  • Ri is -H
  • R 2 and R 3 are independently -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C !
  • each of R 5 and R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -O(C r C ⁇ o)alkyl, -C(O)(C,-do)alkyl, -C(O)NH(CH 2 ) m (C,-C ⁇ o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C ⁇ -C 10 )alkyl(C,-C,o)alkyl), -CO 2 (C,-C ⁇ 0 )alkyl, -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C ]0 )alkynyl, -(C 3 -C ⁇ 0 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C
  • each Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(Ci-C, 0 )alkyl, -C(O)NH(CH 2 ) m (C ⁇ -d 0 )alkyl, -OCF 3 , -benzyl,
  • -CO 2 (CH 2 ) m CH((d-C 1 o)alkyl(C,-C 1 o)alkyl), -CO 2 (d-C 1 o)alkyl, -(C 1 -C 10 )alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -phenyl, naphthyl, -(C 3 -C, 0 )heterocycle, -CO 2 (CH 2 ) m (d-C 10 )alkyl, -CO 2 (CH 2 ) m H, -NHC(O)(d
  • the Edg-2 modulators can also mclude the following compounds:
  • a prefened Edg-2 modulator is a compound of the formula below:
  • the Edg-2 modulators have the structural formula (XXV):
  • each of R! and R 2 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -NH(aryl), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -aryl, -(C 2 -C 10 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 3 -d 0 )cycloalkyl(aryl), -(C 8 -C 14
  • each R 5 and R ⁇ 5 is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • C ⁇ o)alkyl -CO 2 (d-C l0 )alkyl, -(C,-C l0 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C 1 o)cycloalkenyl, -(C 5 )heteroaryl,
  • -N C(aryl), -OC(O)O(d-C 10 )alkyl, or -SO 2 NH 2 ;
  • Ri and R 2 can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6- membered aromatic ring; two R groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the Edg-2 modulator can also preferably be a compound of the structural formula (XXVI):
  • R is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH,
  • each R 5 and Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(d-do)alkyl(C ⁇ -C 10 )alkyl, -O(C,-C, 0 )alkyl, -C(O)(C ⁇ -C ⁇ o)alkyl,
  • R 7 is -CO 2 H, -C(O)(d-C, 0 )alkyl, -C(O)NH(CH 2 ) m (d-C ⁇ 0 )alkyl, -benzyl, -CO 2 (CH2) m CH((C 1 -C 1 o)alkyl(C 1 -do)alkyl), -CO 2 (C 1 -C 1 o)alkyl, -(C 1 -C 1 o)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C 3 -C 10 )cycloalkyl, -(C 8 -C M )bicycloalkyl, -(C 5 -C]o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -phenyl, naphth
  • the Edg-2 modulators can also include the following compounds:
  • the Edg-2 modulators of the invention have the structural formula (XXVII):
  • each of R, and R 2 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -do)alkyl, -(C 2 -C ⁇ 0 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C -C ⁇ o)cycloalkyl, -(C 8 -C] 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -(C 5 -do)heteroaryl, -naphthyl, -(C 3 -do)heter
  • each R and Re is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • Ri is -NH(aryl).
  • the Edg-2 modulator has the structural formula (XXVIII):
  • each of Ri, R 2 and R 4 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 ,
  • -benzyl -CO 2 CH(R 5 )(R 5 ), -(d-C 10 )alkyl, -(C 2 -C ⁇ o)alkenyl, -(d-C ⁇ alkynyl, -(C 3 -do)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl,
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C ⁇ o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C ⁇ -C ⁇ o)alkyl, -C(O)(C ⁇ -C 10 )alkyl, -C(O)NH(CH 2 ) m (C ⁇ -C ⁇ o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C,-do)alkyl(d- C,o)alkyl), -CO 2 (C ⁇ -C ⁇ 0 )alkyl, -(C ⁇ -C 10 )alkyl, -(C 2 -C ⁇ o)alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C !
  • the Edg-2 modulators can also include the following compounds:
  • Michael addition of aromatic amine 3 to maleic anhydride 1 provides amide 5, which may be cyclized (e.g., sodium acetate and acetic anhydride) to yield imide 7.
  • Michael addition of phenylhydroxylamine which may be prepared from nitrobenzene by partial reduction (e.g., Zn, NH 4 C1) gave the desired disubstituted imide 11.
  • a large number of analogues of 11 may be prepared simply by using different amines 3 and or hydroxylamines other than phenyl hydroxylamine.
  • acylated phenol 21 e.g., NBS, AIBN
  • bromide 23 which may be converted to ketone 25 (CrCl 2 ) by internal acyl transfer.
  • Ketone 25 may be acylated to provide benzoate 27, (e.g., benzoyl chloride, dimethylaminopyridine) which can undergo cyclization to give pyrazole 29 (e.g., ethylhydrazine, acetic acid).
  • benzoate 27 e.g., benzoyl chloride, dimethylaminopyridine
  • pyrazole 29 e.g., ethylhydrazine, acetic acid
  • the present invention provides a method of modulating an SI P3 or Edg-3 receptor (e.g., human Edg-3, GenBank Accession No. X83864) mediated biological activity.
  • a cell expressing the Edg-3 receptor is contacted with an amount of an Edg- 3 receptor agonist or antagonist sufficient to modulate an Edg-3 receptor mediated biological activity.
  • Edg-3 is a G protein coupled receptor ("GPCR").
  • GPCR G protein coupled receptor
  • the Edg-3 (S1P3) receptor is encoded by an endothelial differentiation gene and along with related receptors, Edg-1 (SlPl), Edg-5 (S1P2), Edg-6 (S1P4) and Edg-8 (S1P5), binds sphingosine- 1-phosphate (“SIP").
  • SIP sphingosine- 1-phosphate
  • the Edg-3 receptor is a human receptor.
  • the Edg-3 receptor may be expressed by recombinant DNA methods well known to those of skill in the art.
  • Particularly useful cell types for expressing and assaying Edg-3 include, but are not limited to, HTC4 (rat hepatoma cells), RH7777 (rat hepatoma cells), HepG2 (human hepatoma cells), CHO (Chinese hamster ovary cells) and HEK-293 (human embryonic kidney cells).
  • Particularly useful vectors for expressing G-protein receptors include, but are not limited to, pLXSN and pCMV (Clontech Labs, Palo Alto, CA; Invitrogen Corporation, Carlsbad, CA).
  • DNA encoding Edg-3 is well known (e.g., human Edg-3, GenBank Accession
  • DNA encoding human Edg- 3 can be co-transfected with a standard packaging vector, such as those described above, which provides an ecotropic envelope for viral replication, into a packaging cell line such as GP-293 (Clontech Labs, Palo Alto, CA).
  • DNA encoding Edg-3 can be transfected into the EcoPack-293 cell line which has, in addition to gag and pol, the env gene to produce an ecotropic envelope.
  • Both methods i.e., co-transfection with a packaging vector or use of EcoPack-293
  • AmphoPack-293 cell line can be used (Clontech, Palo Alto, CA).
  • a number of natural cell lines naturally express Edg-3 receptors. These include, but are not limited to, CaOV-3 human ovarian cancer cells, MDA-MB-453 and MDA-MB-231 breast cancer cells, HT-1080 human fibrosarcoma, HUVEC cells, OV202 human ovarian cancer cells, Hela human cervical adenocarcinoam cells, HEK293 human embryonic kidney cells, NIH 3T3 mouse fibroblast cells (ATCC, Manassas, VA; Vec Technologies Inc., Rensselaer, NY; Dr. Edward Goetzl, University of California, San Francisco, San Francisco, CA).
  • CaOV-3 human ovarian cancer cells include, but are not limited to, CaOV-3 human ovarian cancer cells, MDA-MB-453 and MDA-MB-231 breast cancer cells, HT-1080 human fibrosarcoma, HUVEC cells, OV202 human ovarian cancer cells, Hela human cervical adenocarcinoam cells, HEK293 human embryonic kidney cells,
  • cells which express the Edg-3 receptor may grown in vitro or may be part of a complex organism such as, for example, a mammal. It is contemplated that the methods of the current invention will be applicable to modulating, e.g., agonizing or antagonizing, Edg-3 receptor activity, regardless of the local environment.
  • cells that express the Edg-3 receptor are grown in vitro (i.e., are cultured).
  • cells that express the Edg-3 receptor are in vivo (i.e., are part of a complex organism).
  • the cells in which the method of the invention may be practiced include, but are not limited to, hepatoma cells, ovarian cells, epithelial cells, fibroblast cells, neuronal cells, cardiac myocytes, carcinoma cells, pheochromocytoma cells, myoblast cells, platelet cells, endothelial cells, keratinocytes and fibrosarcoma cells.
  • the cells in which the invention may be practiced include, but are not limited to, OV202 human ovarian cells, HTC rat hepatoma cells, CAOV-3 and SKOV-3 human ovarian cancer cells, MDA-MB-453 breast cancer cells, MDA-MB- 231 breast cancer cells, HUVEC, Hela human cervical adenocarcinoam cells, HEK293 human embryonic kidney cells, NIH 3T3 mouse fibroblast cells, A431 human epitheloid carcinoma cells, and HT-1080 human fibrosarcoma cells.
  • an Edg-3 receptor mediated biological activity is modulated in a subject or in an animal model.
  • a therapeutically effective amount of an modulator of the Edg-3 receptor is administered to the subject or animal.
  • the subject or animal is in need of such treatment.
  • the biological activity mediated by the Edg-3 receptor may include, for example, calcium mobilization, VEGF synthesis, IL-8 synthesis, platelet activation, cell migration, phosphoinositide hydrolysis, inhibition of cAMP formation or actin polymerization.
  • the biological activity mediated by the Edg-3 receptor also includes, but is not limited to, apoptosis, angiogenesis, wound healing, inflammation, expression of endogenous protein growth factors, cancer invasiveness or atherogenesis.
  • the biological activity mediated by the Edg-3 receptor is cell proliferation, which may lead to enhancement of wound healing; alternatively, it may lead ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer or prostrate cancer.
  • cell proliferation is stimulated by SIP.
  • the biological activity mediated by the Edg-3 receptor may include increasing fatty acids levels (e.g., free fatty acids and lyso- phosphatidylcholine) which may lead to acute lung diseases, such as adult respiratory distress syndrome ("ARDS”) and acute inflammatory exacerbation of chronic lung diseases like asthma.
  • ARDS adult respiratory distress syndrome
  • the present invention provides methods for using Edg-3 antagonists in treating or preventing disorders such as, but not limited to, vasoconstriction in cerebral arteries, autoimmune and related immune disorders, including, but not limited to, systemic lupus erythematosus (SLE), rheumatoid arthritis, non-glomerular nephrosis, psoriasis, chronic active hepatitis, ulcerative colitis, Crohn's disease, Behcet's disease, chronic glomerulonephritis, chronic thrombocytopenic purpura, and autoimmune hemolytic anemia.
  • Edg-3 antagonists can also be used in organ transplantation. Without intending to be bound by any particular mechanism or theory of action, Edg-3 antagonists are believed to be potentially effective immunosuppresive agents because activated T cells express the Edg-3 receptor.
  • Edg-3 agonists and antagonists can be used to treat vascular occlusive disorders.
  • activation of Edg-3 receptors by using an Edg-3 agonist can result in increased vasoconstriction, which is beneficial in conditions such as migraine headaches.
  • Inhibition of Edg-3 by an Edg3 antagonist can be beneficial in conditions such as a stroke, a subarachnoid hemorrhage, or a vasospasm such as a cerebral vasospasm.
  • the modulator exhibits inhibitory selectivity for the Edg-3 receptor. In one embodiment, the modulator exhibits at least about 5 fold inhibitory selectivity for Edg-3 relative to other Edg receptors. Inhibitory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.4 (Example 4), 6.6 (Example 6) and 6.7 (Example 7) respectively. Other assays suitable for determining inhibitory selectivity would be known to one of skill in the art. Preferred assays include the calcium mobilization assay of Section 6.4. In another embodiment, the modulator exhibits at least about 20 fold inhibitory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits at least about 100 fold inhibitory selectivity for Edg-3 relative to other Edg receptors. In another embodiment, the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits about 5 fold to about 200 fold inhibitory selectivity for Edg-3 relative to other Edg receptors. In still another embodiment, the modulator exhibits at least about 5 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits at least about 20 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits at least about 100 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits at least about 200 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits about 5 fold to about 200 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold inhibitory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold inhibitory selectivity for Edg-3 relative to other Edg receptors. In still another embodiment, the modulator of cell proliferation exhibits at least about 5 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold inhibitory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits stimulatory selectivity for the Edg-3 receptor. In one embodiment, the modulator exhibits at least about 5 fold stimulatory selectivity for Edg-3 relative to other Edg receptors. Stimulatory selectivity can be measured by assays such as a calcium mobilization assay or a migration and/or invasion assay or a proliferation assay, for example, as described in Section 6.4 (Example 4), 6.6 (Example 6) and 6.7 (Example 7) respectively. Other assays suitable for determining stimulatory selectivity would be known to one of skill in the art. Preferred assays include the calcium mobilization assay of Section 6.4. In another embodiment, the modulator exhibits at least about 20 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits at least about 100 fold stimulatory selectivity for Edg-3 relative to other Edg receptors. In another embodiment, the modulator exhibits at least about 200 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits at least about 200 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits about 5 fold to about 200 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator exhibits at least about 5 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits at least about 20 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors. In still another embodiment, the modulator exhibits at least about 100 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits at least about 200 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator exhibits about 5 fold to about 200 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold stimulatory selectivity for Edg-3 relative to other Edg receptors.
  • the modulator of cell proliferation exhibits at least about 5 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the modulator of cell proliferation exhibits at least about 20 fold stimulatory selectivity for Edg-3 relative to Edg-1, Edg-5, Edg-6 and Edg-8 receptors.
  • the Edg-3 modulator is not a lipid.
  • the modulator of Edg-3 receptor mediated biological activity does not contain a phosphate group such as a phosphoric acid, a cyclic phosphate ester or a linear phosphate ester.
  • the modulator of the Edg-3 receptor is not a phospholipid.
  • phospholipid includes all phosphate (both phosphate esters and phosphoric acids) containing glycerol derivatives with an alkyl chain of greater 10 carbon atoms or greater, dioctyl glycerol, any N-acyl ethanolamide phosphate derivative (both phosphate esters and phosphoric acids), LPA, SIP or any of their analogues (both phosphate esters and phosphoric acids) (see, e.g., Bandoh, et al, 2000, FEBS Lett. 428, 759; Bittman et al., 1996, J.
  • the modulator is also not a compound of structural formula (XXXIV):
  • X is O or S
  • R 2 o is alkyl, substituted alkyl, aryl, substituted aryl or halo
  • R 21 is alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
  • R 23 is hydrogen, alkyl or substituted alkyl
  • R 24 is aryl, substituted aryl, heteroaryl or substituted heteroaryl
  • R 23 and R 24 form a cycloalkyl ring (International Application No: WO 01/60819).
  • the modulator is not any compound of the formula below:
  • R 2 o, R 2 ⁇ and R 24 are as previously defined.
  • the modulator is not any compound disclosed in International Application No: WO 01/60819.
  • the modulator can be an agonist of the Edg-3 receptor.
  • the agonist can be a weaker agonist than the natural agonist and may compete with the natural agonist for the binding site.
  • the modulator can be an antagonist of the Edg-3 receptor.
  • the Edg-3 modulator can be a biomolecule such as a nucleic acid, protein, (e.g., an enzyme, an antibody, or a soluble Edg-3 receptor polypeptide) or oligosaccharide or any combination thereof.
  • the Edg-3 modulator may be oligomers or monomers of the above biomolecules such as amino acids, peptides, monosaccharides, disaccharides, nucleic acid monomers, dimers, etc., or any combination thereof.
  • the Edg-3 modulator may also be a synthetic polymer or any combination of synthetic polymer with biomolecules including monomers or oligomers of biomolecules.
  • the Edg-3 modulator may also be a small organic molecule.
  • the Edg-3 modulator can be an organic molecule of molecular weight less than 750 daltons.
  • the molecular weight can be about 200 to about 1000 daltons.
  • the molecular weight can be about 200 to about 750 daltons.
  • the molecular weight can be about 200 to about 600 daltons.
  • the molecular weight is about 300 to about 500 daltons.
  • the small organic molecule can be orally administered to a subject. In other embodiments, the small organic molecule is capable of crossing the blood-brain barrier.
  • the modulator may, for example, facilitate inhibition of the Edg-3 receptor through direct binding to the LPA binding site of the receptor, binding at some other site of the Edg-3 receptor, interfering with Edg-3 or LPA biosynthesis, covalently modifying either the LPA or the Edg-3 receptor, or otherwise interfering with Edg-3 mediated signal transduction.
  • the modulator binds to the Edg-3 receptor with a binding constant between about 10 ⁇ M and about 1 fM. In another embodiment, the modulator binds to the Edg-3 receptor with a binding constant between about 10 ⁇ M and about 1 nM.
  • the modulator binds to the Edg-3 receptor with a binding constant between about 1 ⁇ M and about 1 nM. In another embodiment, the modulator binds to the Edg-3 receptor with a binding constant between about 100 nM and about 1 nM. In another embodiment, the modulator binds to the Edg-3 receptor with a binding constant between about 10 nM and about 1 nM. Preferably, the modulator binds to the Edg-3 receptor with a binding constant better (i.e., less) than about 10 nM. In certain embodiments, the modulator is a compound of structural formula
  • n 0 or l
  • o is O, 1, 2, 3 or 4;
  • X is C, NR 7 O or S
  • Y is C, NR 8 O or S
  • Ri is either absent or hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylamino, substituted arylamino, arylsulfonyl, substituted arylsulfonyl, carboxy, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamin
  • R 2 , R 3 and R are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylamino, substituted arylamino, arylsulfonyl, substituted arylsulfonyl, carboxy, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl
  • each R 5 is independently, alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkylthio, substituted alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylsulfonyl, substituted arylsulfonyl, azido, carboxy, carbamoyl, substituted carbamoyl, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, dialkylamino, substitute
  • R 7 and R 8 are independently absent, hydrogen, alkyl, substituted alkyl, acyl or substituted acyl.
  • the modulator is a compound of structural formula (XXXV) or structural formula (XXXVI):
  • R ⁇ is either absent or hydrogen, acyl, substituted acyl, acylamino, substituted acylamino, alkoxycarbonyl, substituted alkoxycarbonyl, alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, arylalkyloxy, substituted arylalkyloxy, carbamoyl, substituted carbamoyl, dialkylamino, substituted dialkylamino, heteroalkyl, or substituted heteroalkyl.
  • R t is either absent or acylamino, substituted acylamino, alkoxycarbonyl, substituted alkoxycarbonyl, arylamino substituted arylamino, or carbamoyl, substituted carbamoyl.
  • Ri is either absent or acylamino, substituted acylamino, arylamino or substituted arylamino.
  • R 2 , R 3 and R 4 are independently alkyl, substituted alkyl, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino, alkoxycarbonyl, substituted alkoxycarbonyl, alkylarylamino, substituted alkylarylamino, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylamino, substituted arylamino, carbamoyl, substituted carbamoyl, dialkylamino, substituted dialkylamino, heteroaryl, substituted heteroaryl, heteroalkyl, or substituted heteroalkyl.
  • R 2 , R 3 and R 4 are independently alkyl, substituted alkyl, acylamino, substituted acylamino, aryl, substituted aryl, arylamino, substituted arylamino, carbamoyl or substituted carbamoyl. More preferably, R 2 , R 3 and R 4 are independently alkyl, substituted acylamino, aryl, substituted arylamino or substituted carbamoyl.
  • each R 5 is independently, alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, amino, aryl, substituted aryl, azido, carboxy, carbamoyl, substituted carbamoyl, cyano, halo, hydroxyl, nitro or thio.
  • each R 5 is independently, alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, azido, carboxy, carbamoyl, substituted carbamoyl, cyano, halo, hydroxyl, nitro or thio.
  • R 7 and R 8 are independently absent, hydrogen, alkyl.
  • the modulator is a compound of structural formula (XXXII):
  • each of Ri, R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-do)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C ⁇ 0 )alkynyl, -(C -do)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C )he
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -(C 5 -do)heteroaryl, -naphthyl, -(C 3 -C ⁇ o)hetero
  • each R 5 and R is independently -halo, -NO 2 , -CN, -OH, -CO 2 H,
  • -CO 2 (CH 2 ) m H, -NHC(O)(C ⁇ -C 10 )alkyl, -NHC(O)NH(C ⁇ -C ⁇ o)alkyl, -NH(aryl), -N C(aryl), -OC(O)O(d-C 10 )alkyl, or -SO 2 NH 2 ;
  • X is O, S, C(R 5 )(R 5 ) or N(R 5 );
  • R] R 2 or R 3 taken in combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • the modulator is a compound of structural formula
  • the Edg-3 receptor modulator is a compound of structural formula (XXXVIII):
  • the Edg-3 receptor modulator has the structural formula (XXXIII):
  • each of R,, R 2 and R 3 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 , -(CH 2 ) m OH, -N(R 5 )(R 5 ), -O(CH 2 ) m R 5 , -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -OCF 3 , -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C ⁇ -C ⁇ o)alkyl, -(C 2 -C,o)alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C -C ⁇ o)cycloalkenyl, -(C
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(d-do)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C 14 )bicycloalkyl, -(C 5 -do)cycloalkenyl, -(Cs)heteroaryl, -(C 6 )heteroaryl, -(C 5 -C ⁇ o)heteroaryl, -naphthyl, -(C 3 -C ⁇ 0 )he
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C,-C,o)alkyl(C ⁇ -C ⁇ o)alkyl, -O(C ⁇ -C,o)alkyl, -C(O)(C,-C ⁇ o)alkyl, -C(O)NH(CH 2 ) m (C,-C,o)alkyl, -OCF 3 , -benzyl, -CO 2 (CH 2 ) m CH((C,-C 10 )alkyl(C 1 - C 10 )alkyl), -CO 2 (C,-C 10 )alkyl, -(d-C 10 )alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -C 10 )alkynyl, -(C 3 -C 1 o)cycloalkyl,
  • X is O, S, or N(R 5 ); Ri, R 2 or R 3 taken in combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6-membered aromatic ring; two R groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging
  • each of Ri , R 2 , R 3 R t , R 7 and R 8 is independently -H, -halo, -NO 2 , -CN, -C(R 5 ) 3 ,
  • R 3 is -H -C(R 5 ) 3 , -(CH 2 ) m OH, -C(O)R 5 , -C(O)NR 5 R 5 , -C(O)NH(CH 2 ) m (R 5 ), -benzyl, -CO 2 CH(R 5 )(R 5 ), -(C,-do)alkyl, -(C 2 -C 10 )alkenyl, -(C 2 -do)alkynyl, -(C 3 -C ⁇ o)cycloalkyl, -(C 8 -C ⁇ 4 )bicycloalkyl, -(C 5 -C ⁇ o)cycloalkenyl, -(C 5 )heteroaryl, -(C 6 )heteroaryl, -(C 5 -C ⁇ heteroaryl, -naphthyl, -(C 3 -C ⁇ o)he
  • each R 5 and Re is independently -H, -halo, -NO 2 , -CN, -OH, -CO 2 H, -N(C 1 -C 10 )alkyl(d-do)alkyl, -O(d-C, 0 )alkyl, -C(O)(C,-C 10 )alkyl,
  • Ri and R2, R2 and R 3 , R 3 and R4, R 4 and R 7 ⁇ or R and R taken in combination can form one or more substituted or unsubstituted 5 or 6 membered cyclic or heterocyclic rings or a 6-membered aromatic ring; two Re groups on adjacent carbon atoms can together form a 5 or 6 membered cyclic or heterocyclic ring or a 6-membered aromatic ring; each m is independently an integer ranging from 0 to 8; and each p is independently an integer ranging from 0 to 5.
  • Preferred Edg-3 modulators include the following compounds:
  • Preferred Edg-3 receptor modulators also include the following compounds:
  • Prefened Edg-3 receptor modulators also include the following compounds:
  • the compounds of the invention may be obtained via the synthetic methods illustrated in Schemes 7, 8, and 9.
  • Starting materials useful for preparing compounds of the invention and intermediates thereof are commercially available or can be prepared by well-known synthetic methods.
  • Other methods for synthesis of the compounds described herein are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (See e.g., Green et al, "Protective Groups in Organic Chemistry", (Wiley, 2 nd ed. 1991); Harrison et al, “Compendium of Synthetic Organic Methods", Vols. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry," Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al, "Reagents for
  • amide 301 Condensation of propiophenone 1 with isatin 3 (i.e., Pfitzinger reaction, KOH, ethanol, heat) provided quinoline 5, which was then acylated with fluoroamine 301 (i.e., carbodiimide, HOBT) to give amide 301.
  • fluoroamine 301 i.e., carbodiimide, HOBT
  • amide 301 analogues of amide 301 may be made by simply reacting substituted propiophenones with substituted isatins and/or acylating the resulting quinoline with different arylamines.
  • the compounds depicted in Schemes 8 and 9 are compounds of structural formula (XXXII).
  • compounds of structural formula (XXXII) may be made by the route depicted in Scheme 2. Reaction of amine 1 with isocyanate 3 in the presence of organic solvents, (e.g., benzene) provides substituted urea 5.
  • organic solvents e.g., benzene
  • a large number of analogues of 5 may be prepared simply by using different amines 1 and/or isocyanates 3.
  • a wide variety of compounds other than the isocyanate 3 depicted may be reacted with amine 1 to provide compounds of the invention.
  • a wide variety of conventional synthetic methods may be used to synthesize compounds of structural Formula (XXXII) other than those depicted above.
  • indolone 15 which may be alkylated, arylated, acylated or sulfonated by treatment with appropriate compounds to provide indolone 17.
  • acid and salt e.g., acetic acid and sodium acetate
  • indolone 15 which may be alkylated, arylated, acylated or sulfonated by treatment with appropriate compounds to provide indolone 17.
  • the alkylation, arylation, acylation or sulfontion can take place at either or both of the location indicated with a dashed bond.
  • analogues of 17 may be prepared simply by using different alkylation, arylation, acylation or sulfontion agents.
  • a wide variety of conventional synthetic methods may be used to synthesize compounds of structural Formula (II) other than those depicted above.
  • Illustrative compounds 305, 307, and 309 are commercially available from
  • Illustrative compounds 301, 311, 313, 315, 319, and 121 are commercially available from Asinex.
  • Compound 317 is commercially available from Chemdiv. 5.9.
  • Therapeutic Uses of the Compounds of the Invention may be used to treat diseases, including but not limited to, ovarian cancer (Xu et al, 1995, Biochem. J. 309 (Pt 3):933-940; Xu et al, 1998, JAMA 280 (8):719-723; Goetzl et al, 1999, Cancer Res.
  • peritoneal cancer endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer and prostrate cancer; acute lung diseases, adult respiratory distress syndrome ("ARDS"), acute inflammatory exacerbation of chronic lung diseases such as asthma (Chilton et al, 1996, J Exp Med 183:2235-45; Arbibe et al, 1998, J Clin. Invest 102:1152-60) surface epithelial cell injury, (e.g., transcomeal freezing or cutaneous bums (Liliom et al, 1998, Am. J.
  • ARDS adult respiratory distress syndrome
  • a compound and/or composition of the invention is administered to a patient, preferably a human, in need of treatment for a disease which includes but is not limited to, the diseases listed above.
  • the compounds and/or compositions of the invention can be administered to a patient, preferably a human, as a preventative measure against diseases or disorders such as those described above.
  • the compounds and/or compositions of the invention can be administered as a preventative measure to a patient having a predisposition, which includes but is not limited to, the diseases listed above.
  • the compounds and/or compositions of the invention may be used for the prevention of one disease or disorder and concurrently treating another disease (e.g., preventing cancer and treating cardiovascular diseases). It is well within the capability of those of skill in the art to assay and use the compounds and/or compositions of the invention to treat diseases, such as the diseases listed above.
  • the compounds and/or compositions of the invention may be advantageously used in medicine, including human medicine.
  • compounds and compositions of the invention are useful for the treatment or prevention of diseases, which include but are not limited to, cancers, including, but not limited to, ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uterine cancer, stomach cancer, small intestine cancer, thyroid cancer, lung cancer, kidney cancer, pancreas cancer, prostrate cancer, acute lung diseases, including, but not limited to, adult respiratory distress syndrome (ARDS) and acute inflammatory exacerbation of chronic lung diseases such as asthma; surface epithelial cell injury, including, but not limited to, transcomeal freezing or cutaneous bums; cardiovascular diseases, including, but not limited to, ischemia and arthesclerosis.
  • diseases include but are not limited to, cancers, including, but not limited to, ovarian cancer, peritoneal cancer, endometrial cancer, cervical cancer, breast cancer, colorectal cancer, uter
  • compounds and/or compositions of the invention When used to treat or prevent disease or disorders, compounds and/or compositions of the invention may be administered or applied singly, in combination with other agents.
  • the compounds and/or compositions of the invention may also be administered or applied singly, in combination with other pharmaceutically active agents, including other compounds and/or compositions of the invention.
  • the current invention provides methods of treatment and prophylaxis by administration to a patient of a therapeutically effective amount of a composition or compound of the invention.
  • the patient may be an animal, is more preferably a mammal, and most preferably a human.
  • the present compounds and/or compositions of the invention are preferably administered orally.
  • the compounds and/or compositions of the invention may also be administered by any other convenient route, for example, by infusion or bolus injection, by abso ⁇ tion through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local.
  • Various delivery systems are known, (e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, etc.) that can be used to administer a compound and/or composition of the invention.
  • Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, particularly to the ears, nose, eyes, or skin.
  • the prefened mode of administration is left to the discretion of the practitioner, and will depend in-part upon the site of the medical condition. In most instances, administration will result in the release of the compounds and/or compositions of the invention into the bloodstream.
  • This may be achieved, for example, and not by way of limitation, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository, or by means of an implant, said implant being of a porous, non-porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.
  • administration can be by direct injection at the site (or former site) of the diseases listed above.
  • Intraventricular injection may be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • a compound and/or composition of the invention may also be administered directly to the lung by inhalation.
  • a compound and or composition of the invention may be conveniently delivered to the lung by a number of different devices.
  • a Metered Dose Inhaler which utilizes canisters that contain a suitable low boiling propellant, (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas) may be used to deliver compounds of the invention directly to the lung.
  • a suitable low boiling propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or any other suitable gas
  • a Dry Powder Inhaler (“DPI”) device may be used to administer a compound and/or composition of the invention to the lung.
  • DPI devices typically use a mechanism such as a burst of gas to create a cloud of dry powder inside a container, which may then be inhaled by the patient.
  • DPI devices are also well known in the art.
  • a popular variation is the multiple dose DPI (“MDDPI”) system, which allows for the delivery of more than one therapeutic dose.
  • MDDPI multiple dose DPI
  • capsules and cartridges of gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch for these systems.
  • Liquid spray devices Another type of device that may be used to deliver a compound and/or a composition of the invention to the lung is a liquid spray device.
  • Liquid spray systems use extremely small nozzle holes to aerosolize liquid drug formulations that may then be directly inhaled into the lung.
  • a nebulizer is used to deliver a compound and/or composition of the invention to the lung.
  • Nebulizers create aerosols from liquid drug formulations by using, for example, ultrasonic energy to form fine particles that may be readily inhaled (see e.g., Verschoyle et al, British J. Cancer 1999, 80, Suppl. 2, 96, which is herein incorporated by reference).
  • Examples of nebulizers include devices supplied by Sheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et al, United States Patent No. 5,954,047; van der Linden et al, United States Patent No. 5,950,619; van der Linden et al, United States Patent No. 5,970,974), Aventis and Batelle Pulmonary Therapeutics.
  • an electrohydrodynamic (“EHD”) aerosol device is used to deliver a compound and/or composition of the invention to the lung.
  • EHD aerosol devices use electrical energy to aerosolize liquid drug solutions or suspensions (see e.g., Noakes et al, United States Patent No. 4,765,539).
  • EHD aerosol devices may more efficiently deliver drugs to the lung than other pulmonary delivery technologies.
  • the compounds of the invention can be delivered in a vesicle, in particular a liposome (see Langer, Science 1990, 249:1527-1533; Treat et al, in "Liposomes in the Therapy of Infectious Disease and Cancer," Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); see generally “Liposomes in the Therapy of Infectious Disease and Cancer,” Lopez-Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989)).
  • the compounds of the invention can be delivered via sustained release systems, preferably oral sustained release systems.
  • a pump may be used (see Langer, supra; Sefton, 1987, CRC Crit Ref Biomed. Eng. 14:201; Saudek et al, N. Engl. J Med. 1989, 321 :574).
  • polymeric materials can be used (see “Medical Applications of Controlled Release,” Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); “Controlled Drug Bioavailability,” Drug Product Design and
  • polymeric materials are used for oral sustained release delivery.
  • enteric-coated preparations can be used for oral sustained release administration.
  • osmotic delivery systems are used for oral sustained release administration (Verma et al, Drug Dev. Ind. Pharm.
  • a controlled-release system can be placed in proximity of the target of the compounds and/or composition of the invention, thus requiring only a fraction of the systemic dose (see, e.g. Goodson, in "Medical Applications of Controlled Release,” supra, vol. 2, pp. 115-138 (1984)).
  • Other controlled-release systems discussed in Langer, 1990, Science 249:1527-1533 may also be used.
  • compositions contain a therapeutically effective amount of one or more compounds of the invention, preferably in purified form, together with a suitable amount of a pharmaceutically acceptable vehicle, so as to provide the form for proper administration to a patient.
  • the compounds of the invention and pharmaceutically acceptable vehicles are preferably sterile.
  • Water is a prefened vehicle when the compound of the invention is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid vehicles, particularly for injectable solutions.
  • Suitable pharmaceutical vehicles also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents or pH buffering agents.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents may be used.
  • compositions comprising a compound of the invention may be manufactured by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate processing of compounds of the invention into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the pharmaceutically acceptable vehicle is a capsule (see e.g., Grosswald et al, United States Patent No. 5,698,155).
  • suitable pharmaceutical vehicles have been described in the art (see Remington's Pharmaceutical Sciences, Philadelphia College of Pharmacy and Science, 17th Edition, 1985).
EP03710713A 2002-01-18 2003-01-21 Verfahren zur behandlung von mit einem edg-rezeptor assoziierten krankheitszuständen Withdrawn EP1513522A2 (de)

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