Merck + Co., Inc.

Louis Kaplan

Prakash S Masurekar

Kevin M Byrne

Jimmy M Fountoulakis

Jerrold M Liesch

David F Sesin

Shieh-Shung T Chen

Byron H Arison

Robert T Goegelman

Ali Shafiee

Carol F Wichmann

Deborah L Zink

Otto D Hensens

Raymond F White

Robert A Giacobbe

Linda S Wicker

Brian R Petuch

David A Boulton

Francis J Dumont

John G MacConnell

Mary N Omstead

Vincent P Gullo

Jennifer Nielsen Kahn

Jan S Tkacz

Lawrence F Colwell, Jr

Robert P Borris

Margaret S Sosa

Patricia M Cameron

Haideh Motamedi

Richard J Monaghan

Described is a new immunosuppressant, L-687,819, a C-31 demethylated derivative of L-683,795 (FK-523), produced under fermentation conditions utilizing the new mutant microorganism, Streptomyces hygroscopicus subsp. ascomyceticus (Merck Culture Collection MA 6646) ATCC No. 53855, being a blocked mutant of Streptomyces hygroscopicus subsp. ascomyceticus (MA 6475) ATCC No. 14891. The macrolide immunosuppressant is useful in preventing human host rejection of foreign organ transplants, e.g. bone marrow and heart transplants.

Microbial immunoregulant

A process for producing an antibiotic compound which is normally a minor component in the cultivation of Z. arboricola to be the major product is described.

Process for production of an antibiotic compound with Zalerion arboricola

Disclosed are new Aspergillus niger mutants which can be used for identifying active FK-506/ rapamycin type, or cyclosporin A type inununosuppressants in a broth, natural product extract, or composition exhibiting inununosuppressant activity. Specifically disclosed are the new mutants, ATCC No. 74085 (MF 5659), which is sensitive to FK-506 and rapamycin but resistant to cyclosporin A; ATCC No. 74086 (MF 5659) which is resistant to FK-506, cyclosporin A and rapamycin; and ATCC No. 74087 (MF 5661) which is resistant to FK-506 and rapamycin, but sensitive to cyclosporin A.

Aspergillus niger mutants

Compounds of Structural Formula (I) ##STR1## are produced by directed biosynthesis. These compounds are squalene synthetase inhibitors and thus useful as cholesterol lowering agents, antifungal agents and cancer treatment agents.

Cholesterol lowering compounds produced by directed biosynthesis

Described is a new enzyme, 31-O-desmethyl-FK-506 O-methyltransferase (FKMT) and its N-terminal amino acid sequence. This enzyme can specifically and preferentially methylate the C-31 hydroxy group in 31-O-desmethyl FK-506/FR-900506 and other 31-O-desmethyl analogs of FK-506/FR-900506 and related compounds such as 31-O-desmethyl immunomycin type molecules, also designated FK-520 and FR-900520 by Fujisawa. The enzyme can be isolated from a FK-506 producing microorganism Streptomyces sp. (Merck Culture Collection No. MA 6858) ATCC No. 55098. Employing the enzyme in its active form, supplemented with Mg.sup.+2 ion, in the presence of the methyl donor, S-adenosyl methionine (SAM), derivatives of 31-O-desmethyl FK-506, 31-O-desmethyl FK-520 and related 31-O-desmethyl compounds may be prepared.

Methlating enzyme from streptomyces MA6858

Compounds of Structural Formula (I) ##STR1## are produced by directed biosynthesis. These compounds are squalene synthetase inhibitors useful as cholesterol-lowering agents.

Directed biosynthesis of cholesterol lowering compounds

A new antibiotic cyclic lipopeptide and a method of producing it are described. The agent has very high activity against human pathogens and is of very low mammalian toxicity.

Process for producing a cyclic lipopeptide employing zalerion arboricola

Described is a process for producing a new immunosuppressant, a C-31 desmethyl, C-19/C-22 cyclic hemiketal biotransformation analog (Compound I) of FR-900520, under novel fermentation conditions utilizing the novel microorganism, Streptomyces, lavendulae ATCC No. 55209. Also disclosed is the C-31 methylated devivative (Compound II) of Compound I produced by enzymatic methylation using 31-O-desmethylimmunomycin O-methyl transferase, (DIMT), a methyl transferase enzyme. The macrolide immunosuppressants are useful in preventing human host rejection of foreign organ transplants, e.g. bone marrow, liver, lung, kidney and heart transplants.

C-31 methylated FR-900520 cyclic hemiketal immunosuppressant agents

Disclosed is a novel lipophilic macrolide of Formula I: ##STR1## The compound of assigned Formula I is an analog of rapamycin which has activity as an antifungal agent and as an immunosuppressant.

Lipophilic macrolide useful as an immunosuppressant

Antibiotic agents

An antibiotic agent produced by the cultivation of Zalerion arboricola which is a cyclic lipopeptide with very high activity against human pathogens and of very low mammalian toxicity and its production and isolation are described.

Antibiotic agent produced by the cultivation of Zalerion microorganism

There are disclosed certain new compounds related to C-076 compounds which have been produced by a mutant of the culture that produced the original C-076 compounds and isolated from the fermentation broth thereof. The compounds retain the C-076 16-membered cyclic backbone, however, the groups attached thereto are considerably modified from the original C-076 compounds. The new compounds have been found to retain the biological activity of the parent C-076 compounds. The compounds are thus potent antiparasitic agents and compositions and methods for such uses are also disclosed.

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New City, NY, United States of America

Louis Kaplan