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US 5,665,704 AGranted
Receptor specific atrial natriuretic peptides
AssigneeGenentech, Inc.
InventorsDavid Lowe, Brian C. Cunningham, David Oare, Robert S. McDowell, John Burnier
Life of this patent
Estimating the term…
Abstract
Human receptor selective atrial natriuretic factor variants containing various substitutions, especially G16R, show equal potency and binding affinity for the human A-receptor but have decreased affinity for the human clearance or C-receptor. These ANF variants have natriuretic, diuretic and vasorelaxant activity but have increased metabolic stability, making them suitable for treating congestive heart failure, acute kidney failure and renal hypertension.
Claims14
A compound represented by Formula (I) ##STR5## where X is selected from the group consisting of H, C.sub.1 -C.sub.6 alkanoyl, Ser-Pro-Lys-, Thr-Ala-Pro-Arg-(SEQ ID NO:
- 1) and C.sub.1 -C.sub.6 alkanoyl-Thr-Ala-Pro-Arg-(SEQ ID NO:
- 1);
- AA.sub.1 is absent or is selected from the group consisting of Ser, Met, Gly, Asp, Ala, Tyr and His;
- AA.sub.2 is absent or is selected from the group consisting of Leu, Asp, Met, Val, Ser, Ala, Phe, Pro and Lys;
- AA.sub.3 is absent or is selected from the group consisting of Cys, Glu, Ser, Gln, His, Gly, Arg and Asp;
- AA.sub.4 is absent or is selected from the group consisting of Arg, Gly, Ala, Asp, Met, Leu, Tyr and Pro;
- AA.sub.5 is absent or is selected from the group consisting of Ser, Cys and Asp;
- AA.sub.6 is absent or is selected from the group consisting of Ser, Gly and Glu;
- AA.sub.7 is selected from the group consisting of Cys, N-methyl-Cys, D-Cys and Pen;
- AA.sub.8 is selected from the group consisting of Phe, N-methyl-Phe, Trimethylphenyl-Ala, halo(F, Cl, Br and I)phenyl-Ala, Trifluoromethylphenyl-Ala, Tyr, O-methyl-Tyr, Cha, .beta.-napthyl-Ala, .alpha.-napthyl-Ala, biphenyl-Ala, diphenyl-Ala, D-Ala, dibenzyl-Ala, florenyl-Ala, adamantyl-Ala, and .alpha.-napthyloxy-Ala;
- AA.sub.9 is selected from the group consisting of Gly, Arg, Thr, Val, Asp, Ala, D-Ala, Pro and Glu;
- AA.sub.10 is selected from the group consisting of Gly, Arg, Ser, Ala, His, Pro and Lys;
- AA.sub.11 is selected from the group consisting of Arg, Lys, N-methyl-Arg, Asp, Ser and Pro;
- AA.sub.12 is selected from the group consisting of Met, Ile, D-Leu, Nle and Leu;
- AA.sub.13 is selected from the group consisting of Asp and Glu;
- AA.sub.14 is selected from the group consisting of Arg, N-methyl-Arg, Pro and Ser;
- AA.sub.15 is selected from the group consisting of Ile, N-Methyl-Ile and Leu;
- AA.sub.16 is selected from the group consisting of Gly, Tyr, Phe, Ser, Pro and a positively charged amino acid residue selected from Orn, Har, Lys, .rho.-amidinophenyl-Ala and Arg;
- AA.sub.17 is selected from the group consisting of Ala, Ser, N-methyl-Ala, and Pro;
- AA.sub.18 is selected from the group consisting of Gln, Ser and homo-Cys;
- AA.sub.19 is Ser;
- AA.sub.20 is selected from the group consisting of Gly and Ala;
- AA.sub.21 is Leu;
- AA.sub.22 is selected from the group consisting of Gly and Ala;
- AA.sub.23 is Cys;
- AA.sub.24 is Asn;
- AA.sub.25 is selected from the group consisting of Ser and Val;
- AA.sub.26 is selected from the group consisting of Phe, D-Phe, N-methyl-Phe and Leu;
- AA.sub.27 is selected from the group consisting of Arg, Orn, Har, Lys, .rho.-amidinophenyl-Ala and Arg-Arg;
- AA.sub.28 is selected from the group consisting of Tyr, Arg, Orn, Har, Lys, .rho.-amidinophenyl-Ala, and homoCys;
- and
- Z is selected from the group consisting of OH and NR.sup.1 R.sup.2 where R.sup.1 and R.sup.2 are independently selected from the group consisting of
- H, C.sub.1 -C.sub.4 alkyl, C.sub.6 -C.sub.12 aryl and C.sub.6 -C.sub.12 aryl-C.sub.1 -C.sub.6 alkyl;
- and where the amide bond (--C(.dbd.O)--NH--) bonding residues AA.sub.7 and AA.sub.8 may optionally be replaced with an amide isostere selected from the group consisting of
- --CH.sub.2 --NH--,
- --CH.sub.2 --S--,
- --CH.sub.2 --S(O).sub.n --, where n is 1 or 2,
- --CH.sub.2 --CH.sub.2 --,
- --CH.dbd.CH-- (E or Z),
- --C(.dbd.O)--CH.sub.2 --,
- --CH(CN)--NH--,
- --C(OH)--CH.sub.2 --, and
- --O--C(.dbd.O)--NH--
- provided that at least two of AA.sub.9, AA.sub.11, and AA.sub.16 are selected according to the following scheme
- AA.sub.9 is Arg, Thr or Glu;
- AA.sub.11 is Asp, Ser or Pro;
- and
- AA.sub.16 is a positively charged amino acid residue selected from the group consisting of
- Arg, homoArg, Lys, Orn, and .rho.-amidinophenyl-Ala;
- and pharmaceutically acceptable salts thereof.
47 more elements
A compound represented by Formula (II) (SEQ ID NO:
- 47) ##STR6## where X is selected from the group consisting of H, C.sub.1 -C.sub.6 alkanoyl, and Thr-Ala-Pro-Arg-(SEQ ID NO:
- 1);
- AA.sub.3 is selected from the group consisting of Arg or Asp;
- AA.sub.7 is selected from the group consisting of Cys, N-methyl-Cys, D-Cys and Pen;
- AA.sub.8 is selected from the group consisting of Phe, N-methyl-Phe, trimethylphenyl-Ala, fluorophenyl-Ala, trifluoromethylphenyl-Ala, Tyr, O-methyl-Tyr, Cha, .beta.-napthyl-Ala, .alpha.-napthyt-Ala, biphenyl-Ala, diphenyl-Ala, dibenzyl-Ala, florenyl-Ala, adamantyl-Ala, 2-thienyl-Ala and .beta.-napthyloxy-Ala;
- AA.sub.9 is selected from the group consisting of Gly, Arg, Thr, Val, Asp and Glu;
- AA.sub.10 is selected from the group consisting of Gly, Arg, Ser, Ala, His and Lys;
- AA.sub.11 is selected from the group consisting of Arg, Asp, Ser and Pro;
- AA.sub.12 is selected from the group consisting of Met, Ile, D-Leu, Leu and Nle;
- AA.sub.14 is selected from the group consisting of Arg and Ser;
- AA.sub.16 is selected from the group consisting of Gly, Phe, Tyr, and a positively charged amino acid residue selected from Orn, Har, Lys, .rho.-amidinophenyl-Ala and Arg;
- AA.sub.18 is selected from the group consisting of Gln and homoCys;
- AA.sub.28 is selected from the group consisting of Tyr and homoCys;
- and
- Z is selected from the group consisting of OH and NH.sub.2 ;
- and where the amide bond (--C(.dbd.O)--NH--) bonding residues AA.sub.7 and AA.sub.9 may optionally be replaced with an amide isostere selected from the group consisting of
- --CH.sub.2 NH--,
- --CH.sub.2 --S--,
- --CH.sub.2 --S(O).sub.n --, where n is 1 or 2,
- --CH.sub.2 --CH.sub.2 --,
- --CH.dbd.CH-- (E or Z),
- --C(.dbd.O)--CH--,
- --CH(CN)--NH--,
- --C(OH)--CH.sub.2 --, and
- --O--C(.dbd.O)--NH--
- provided that at least two of AA.sub.9, AA.sub.11, and AA.sub.16 are selected according to the following scheme
- AA.sub.9 is Arg, Thr or Glu;
- AA.sub.11 is Asp, Ser or Pro;
- and
- AA.sub.16 is a positively charged amino acid residue selected from the group consisting of
- Orn, homoArg, Lys, .rho.-amidinophenyl-Ala and Arg;
- and pharmaceutically acceptable salts thereof.
29 more elements
A human ANF variant selected from the group consisting of
- hANF(1-28) G9T, R11S, M12I;
- hANF(1-28) G9R, R11D, M12I, G16R;
- hANF(1-28) G9T, R11S;
- hANF(1-28) G9E, G10R, R11lP;
- hANF(1-28) G10K, R11S;
- hANF(1-28) M12I, G16R;
- hANF(1-28) G9T, R11S, G16R, Q18P;
- hANF(TAPR 1-28) M12I, G16R;
- hANF(1-28) M12I, R14S, G16R;
- hANF(1-28) G9E, G10R, R11P, M12I, G16R;
- hANF(1-28) R3D, G9T, R11S, M12L, R14S, G16R;
- hANF(1-28) G9T, R11S, M12I, G16R, inserting D-Ser between residues 7 and 8;
- hANF(1-28) G9T, R11S, M12I, G16R, inserting D-Ala between residues 7 and 8;
- hANF(TAPR1-28) G9T, R11S, M12I, G16R;
- hANF(1-28) F8Cha(1-cyclohexylalanine), G9T, R11S, M12I, G16R;
- Mpa(mercaptopropionic acid), hANF(8-28) G9(D-Thr), R11S, M12I, G16R;
- Mpa (mercaptopropionic acid), hANF(8-28) G9(D-Ala), R11S, M12I, G16R;
- bANF(1-28) C7(N-MeCys), G9T, R11S, M12I, G16R;
- hANF(1-28) F8(N-MePhe), G9T, R11S, M12I, G16R;
- hANF(1-28) C7F8 replaced by C(.psi.CH.sub.2 NH)F, G9T, R11S, M12I, G16R;
- hANF(1-28) G9(D-Ala), R11D, M12I, G16R;
- hANF(1-28) F8Phg(D- or L-phenyl glycine), G9T, R11S, M12I, G16R;
- hANF(1-28) R3D, G9T, R11S, M12L, R14S, G16R, Q18C, Y28C;
- and
- hANF(1-28) M12I, G16R, A17E, Q18A.
22 more elements
Dependencies are inferred from the claim text.