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r MEMORANDUM TO: Dr. H. J. Minnemeyer FROM: R. S. Marmor SUBJECT: PMO Analogs History of Project _ March 31, 1977 On September 8, 1975, I proposed in a memo to you that we initiate a structure activity relationship study on PMO by preparing a number of analogs of PMO and arrang- ing to have a ciliastasis remission bioassay perforn,ad. For a commitment of relatively few man-hours, this would give us valuable information as to whether more potent PMO analogs exist, on the molecular nature of the bio- activity, and a better stance in patent protection. Over the next few months, 21 analogs were prepared. Most were observed to have less intense and more Aleas2nt odors than PMO. ~ In a memo on April 13, 1976, I listed the 21 compounds we prepared and informed you that Dr. Tong had an interest in evaluating PMO and analogs for ciliastasis remission activity by an approach different than that employed by Prof. Dalhamn. On talking further with Dr. Tong, he stated that once the system was built and operable, the testing of the analogs could be quickly performed. Dr. Schultz requested at that time that when data was available supporting activity of the analogs, we should consider expanding the scope of existing patents. On July 2, 1976, my memo to Dr. Tong stated we were ready to supply him with any samples whenever he could begin. Memos from Dr. Tong to you on October 1, 1976 and from Mr. Heck to you on November 2, 1976, indicated that the apparatus would soon be ready to begin bioassay. On March 14, 1977 in Lorillard Report #973, Dr. Tong reported on the absence of mutagenicity and high dose toxicity C for 20 of the PMO analogs. ~ ~ N FA O

d Dr. H. J. Minr.emeyer - 2 - March 31, 1977 Current Status Control data for the chicken trachea ciliastasis remission experiment is presently being gathered. When this phase is complete, PMO will be studied, then testing will begin on the analogs. Further work on any active analogs would be anticipated. It is my opinion, drawn from the history of this project and the present priority level this project is being given, that there is little chance of having completed analog data in hand by the end of this year. Proposed Further Work It is premature to discuss further experiments at this time. The question now is, are there analogs of greater activity than PMO? If there are, we expect that they can be employed on cigarettes at lower dose levels such that the flavor and delivery problems will disappear. Will these more desirable analogs be without undesirable physiological effects such as bronchiodilation? Are we to ignore research on these analogs because additional biological testing would be costly and time-consuming? The trend in cigarettes to low tar-high filtration design further increases the need to investigate PMO analogs. 94, lGG[4,vrZ-- R. . Marmor RSM/lmh Xc: Dr. F. J. Schultz