Synthetic vasoactive intestinal peptide analogs
AssigneeHoffmann-La Roche Inc.
InventorsDavid R. Bolin, Johannes A. Meienhofer, Iou-Iou Sytwu
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Abstract
Novel vasoactive intestinal peptide analogs containing substitutions of appropriately selected amino acids at specific positions of the VIP molecule, with potent sustained bronchodilatory activity without cardiovascular side effects.
Claims29
A compound of the formula
- X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4
- wherein R represents Asn or Ala;
- R.sub.1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg;
- R.sub.2 represents Leu, Ile or Nle;
- R.sub.3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val;
- R.sub.4 represents Asn-NH.sub.2 or Thr-NH.sub.2 ;
- and X represents hydrogen or acetylation at the amino terminal, provided that when R.sub.1 is Thr-Arg-Leu-Arg, R may not equal Nle,
- and the pharmaceutically acceptable acid or base addition salts thereof.
A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula
- X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4
- wherein R represents Asn or Ala;
- R.sub.1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg;
- R.sub.2 represents Leu, Ile or Nle;
- R.sub.3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val;
- R.sub.4 represents Asn-NH.sub.2 or Thr-NH.sub.2 ;
- and X represents hydrogen or acetylation at the amino terminal, provided that when R.sub.1 is Thr-Arg-Leu-Arg, R.sub.2 may not equal Nle, in an amount
- sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.
A pharmaceutical composition for the treatment of bronchotracheal constriction disorders in humans comprising a compound of the formula
- X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-Nle-Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4
- wherein R represents Asn or Ala;
- R.sub.1 represents Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg;
- R.sub.2 represents Leu, Ile or Nle;
- R.sub.3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val;
- R.sub.4 represents Asn-NH.sub.2 or Thr-NH.sub.2 ;
- and X represents hydrogen or acetylation at the amino terminal, in an amount
- sufficient to relax bronchotracheal smooth muscle and a pharmaceutically acceptable carrier.
A method of treating bronchotracheal constriction disorders which comprises administering a compound of the formula
- X-His-Ser-Asp-Ala-Val-Phe-Thr-Asp-R-Tyr-R.sub.1 -Lys-Gln-R.sub.2 -Ala-Val-Lys-Lys-Tyr-Leu-R.sub.3 -Leu-R.sub.4
- wherein R represents Asn or Ala;
- R.sub.1 represents Thr-Arg-Leu-Arg, Thr-Lys-Leu-Lys, Thr-Arg-Leu-Lys, Thr-Orn-Leu-Arg, Ser-Arg-Phe-Arg or Thr-Lys-Leu-Arg;
- R.sub.2 represents Leu, Ile or Nle;
- R.sub.3 represents Asn-Ser-Ile, Asn-Thr-Ile, Thr-Ser-Ile or Asn-Ser-Val;
- R.sub.4 represents Asn-NH.sub.2 or Thr-NH.sub.2 ;
- and X represents hydrogen or acetylation at the amino terminal, provided that when R.sub.1 is Thr-Arg-Leu-Arg, or R.sub.2 may not equal Nle
- in an amount sufficient to relax bronchotracheal smooth muscle.
A method of treating bronchotracheal constriction disorders according to claim 25 wherein R.sub.2 is Nle.
Dependencies are inferred from the claim text.