Smithkline Beckman Corporation

Smithkline Beecham Corporation

Smithkline Beechman Corporation

Michael L Moore

William F Huffman

James Francis Callahan

Nelson C Yim

Kenneth Allen Newlander

Dennis Shinji Yamashita

Garland R Marshall

Joseph Weinstock

John Duncan Elliott

Fadia E Ali

Balan Chenera

William M Bryan

Solid phase combinatorial synthesis is carried out in a multi-reactor synthesizer comprising an array of separate reactor cells (,) containing a solid reaction support medium (,). Subsets of the reactor cells (,) are interconnected with one another in a desired pattern, and, in a first reaction step, reagents (A, B, C) are circulated through the subsets. After the first reaction step is completed, the reactor cells (,) are rearranged into a new configuration of the subsets, and the same, or other, reagents (A, B, C) are circulated through the new subsets. The process can be repeated to produce large numbers of compounds differing from one another.

Multi-reactor synthesizer and method for combinatorial chemistry

Cyclic penta- and hexa-peptide libraries containing one or more known amino acids, one or more randomized amino acids and a conformationally constraining element are disclosed. These peptide libraries may be used for screening for new bioactive peptides and for elucidating structural information pertinent to drug design.

Cyclic semi-random peptide libraries

Silyl linker for solid phase organic synthesis of aryl-containing

Solid phase combinatorial synthesis is carried out in a multi-reactor synthesizer comprising an array of separate reactor cells containing a solid reaction support medium. Subsets of reactor cells are interconnected with one another in a desired pattern, and, in a first reaction step, reagents are circulated through the subsets. After the first reaction step is completed, the reactor cells are rearranged into a new configuration of subsets, and the same, or other, reagents are circulated through the new subsets. The process can be repeated to produce large numbers of compounds differing from one another.

Compounds and methods

HIV protease inhibitors

Vasopressin-like peptide whose structures have been modified by an alpha-methyl amino acid at the 4 or 7 position are set forth. These compounds have potent vasopressin antagonist activities.

Vasopressin compounds

Certain vasopressin-like compounds whose structures have a .beta.,.beta.-diethyl-.beta.-mercaptopropionic acid at position 1 have unexpectedly potent V.sub.2 -antagonist activity. A species of the group is [1-.beta.,.beta.-diethyl-.beta.-mercaptopropionic acid)-2-(O-ethyl-D-tyrosine)-4-valine-8-arginine-9-desglycine]vasopressin.

Peptides whose structures resemble those of vasopressin antagonists but have both a carboxamido amino acid unit and a basic amino acid unit in the side chain have good antagonist activity. A species of the invention is [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-8-glutamine-9-desglycine]-vasopressi n.

GLN- or ASN-vasopressin compounds

Vasopressin derivatives having unexpected VSP site binding activity whose structures are characterized by a Mpr unit at position 1 and a Pen unit at position 6 are prepared by standard peptide synthetic methods also using an oxidative cyclization of a linear peptide dimercaptan. A representative species is [1-.beta.-mercaptopropionic acid-2-(O-ethyl)-D-tyrosine-4-valine-6-penicillamine-8-arginine]vasopressi n.

6-pen-vasopressin compounds

Peptides having vasopressin antagonist activity are prepared by a peptide synthesizer to insert a N-methylarginine at the 7-position of the structure. An example of this series of compounds is [1-(.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)-2-(O-ethyl-D-tyrosine)-4-valine-7-desproline-8-N-methylarginine-9-de sglycine]-vasopressin.

Des-proline-N-methylarginine vasopressins

Certain vasopressin-like peptides, which have an acyclic unit at position 1 and which have an .omega.-amino- or guanidinoalkyl substituent attached to the cysteine in the 6-position of the ring, have V.sub.1 -vasopressin and oxytocin antagonist activity. A species of this series of new compounds is [1-desaminopenicillamine-2-(O-ethyl-D-tyrosine)-8-(1,4-diaminobutane)-9-de sglycinamide]-vasopressin.

Methods of producing vasodilation or antioxytocic activity

Polypeptide intermediates

Certain new vasopressin-like peptides which have structures characterized by having a bisaminoalkylbenzene present in the vasopressin tail at the 7- or 8-position retain vasopressin antagonist activity. A species of the invention is [1-.beta.-mercapto-.beta.,.beta.-cyclopentamethylenepropionic acid)-2-(O-ethyl)-D-tyrosine-4-valine-8-1',4'-bis(aminomethyl)benzene-9-de sglycinamide]-vasopressin.

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Media, PA, United States of America

Michael L Moore