276 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS TaBt, E 4 (Continued) Tetradecylamine .................................................. s/10 Tetraethylene pentamine ........................................... 1.0 1,2,3,4-Tetrahydrocarbazole ........................................ s/10 N,N'-Tetrahydroxypropyl ethylene diamine .......................... 0.1 1-Phenyl-5~[1-methylamine-ethyl] tetrazole ........................... 0.1 Triallyl cyanurate ................................................. s/10 2,4,6-Tri (di(2-ethylhexyl) aminomethyl) phenol ....................... s/2 pg 2,4,6-Tri (dimethylaminomethyl) phenol ............................. 1.0 pg Recoveries over 100 per cent Alkyl pyridines HB ............................................... s/10 2-Amino-2-methyl-1, 3-propanediol .................................. 0.1 4-Aminophenol ................................................... 0.1 P-Aminophenyl phosphoric acid ..................................... s/10 3-Amino-propanol ................................................. 0.1 2-Aminopyridine .................................................. s/10 Amyl cyclohexyl ammonium oleate .................................. 0.1 1-(0-Anisyl)-3-diethylamino-2-propanol HCl .......................... 0.01 Benzylamine ...................................................... 1.0 Benzylidene quinaldine ............................................ 0.1 N-Butylamine .................................................... 0.1 4-Butyl (5 or 6) methylpiperazine ................................... 0.1 Cyclohexylaminoethanol ........................................... 0.1 1-Cyclohexylamino-2-propanol ...................................... 0.1 pg 3,5-Dicarbethoxy-2,6-dimethyl-4-propyl-l,4 dihydropyridine ............ s/10 Diethylamine ..................................................... 1.0 B-Diethylaminoethanol ............................................ 0.1 B-Diethylamino propylamine ....................................... 1.0 Diethyl N,N'-ethylene di(B-amino-crotonate) ........................ s/10 6,7-Dimethoxy-l,2,3,4-tetrahydro isoquinoline ........................ 0.02 N,N-Dimethylhexadecylamine ...................................... s/10 2,6-Dimethyl-4-octadecyl-morpholine ................................ 0.1 Di (2,5-dimethyl pyrryl) ethane ..................................... s/10 Ethanol amine .................................................... 0.1 Di (2-ethylhexyl) ethylenediamine ................................... 0.1 Dioctadecylamine ................................................. s/10 N-Diphenylmethyl, N'-ip-ethoxybenzyl piperazine ..................... s/10 2-(l-E thylamyl)-3-(2-etnylhexyl) oxazolidine .......................... s/10 Ethylenediamine q- 50 M propylene oxide q- 200 M ethylene oxide ..... 0.1 Ethylenediamine q- 100 M propylene oxide q- 100 M ethylene oxide .... 0.1 1-(2-Ethylhexyl)-2-heptadecyl glyoxalidine ........................... s/10 N-Fluorene-N'-methyl piperazine dihydrobromide ..................... 0.1 2 Hepta decyl-l-(hydroxyethyl)-l,4,5,6-tetrahydropyrimidine ........... s/10 1,6-Hexanediamine ................................................ 1.0 3,3' Iminobispropylamine .......................................... 1.0 B-Isobutylaminoethanol ........................................... 0.1 N-Isobu tyldiethanolamine .......................................... 1.0 3-Methoxypropylamine ............................................ 1.0 N-Methyldiethanolamine .......................................... 1.0 1-Methyl 2,2-di(methoxyethoxy) ethylamine .......................... s/2 pg 4,4'-(Methylene-dioxydiethyl) di-morpholine ......................... 0.1 Monocaine formate ................................................ 0.1 Monoisopropanolamine ............................................ 0.1 N,N'-Di (4-morphylpropyl)-piperazine ............................... 0.1 Nicotine sulfate solution 40% ...................................... s/10 N-Octadecyl pyrrolidine ........................................... s/10 2-Phenylbenzoxazole .............................................. 0.1 Phenyl biguanide hydrochloride ..................................... 0.1 N-Phenyl-N'-methylpiperazine maleic acid salt ....................... 0.1 4-Phenylsemicarbazide HCl ......................................... s/10 Rosin amine D plus two moles ethylene oxide ........................ s/2 Tallow amine ..................................................... s/10 N,N,N',N'-Tetra butylmethylene diamine ........................... 1.0 Triisopropanol amine ........................................... 0.1
ENZYME INHIBITORS FOR DENTIFRICES 277 rapidity of penetration should be tested for their duration of action beyond the one-hour period which is the safe limit of extrapolation from the primary screening method. Inhibitors for use in dentifrice should have an action which lasts for twelve hours, the usual interval between the customary morning and evening brushing, and inhibition can be studied for twelve hours with the procedure we have described. With these two screening principles the ten most active compounds could be selected from the original hundred. The ten would certainly deserve initial study of toxicity. Any toxic substance could be replaced by com- pounds that rank next highest by in vitro tests, then the ten could be studied without undue cost by means of plaque pH drop tests used by Stephan (12) and others. The ten compounds might also be used for evaluation on dental caries activity with hamsters or rats. The best of the ten could be selected for clinical trial on the basis of a wide variety of data on inhibitory action. SUMMARY The aims, scope, and methods of an Inhibitor Survey Program have been described, and some background has been presented regarding the assump- tions that dental investigators make in their search for inhibitors for denti- frice use. Examples have been given of the findings with amines. Twenty active amines were selected from a group of 156 tested. Compounds ca- pable of inhibiting acid production were generally alkylated amines, ethylene diamines, imidazolines, or piperazines. It is recommended that these and other chemicals be examined next for their effectiveness during short contact with a synthetic dental plaque, and for the duration of their action. The substances which show rapid penetra- tion and good retention deserve to be investigated by toxicity and other in vivo studies. This approach is suggested as an efficient means of selecting one compound from a large group of substances that appear promising from primary screening methods. REYERENC•S (1) Fosdick, L. S., •. Am. Dent. Assoc., 40, 133 (1950). (2) Zander, H. A., Ibid., 40, 569 (1950). (3) Hill, T. J., Rasch, C., and Wollpert, B., •7. Dent. Res., 32, 453 (1953). (4) Stephan, R. M., Ibid., 22, 63 (1943). (5) Bibby, B. G., Ibid., 24, 297 (1945). (6) Muhler, J. C., Nebergall, W. H., and Day, H. G., Ibid., 33, 33 (1954). (7) Nevin, R. B., Walsh, J.P., and King, R. M., N. Z. Dent. 7., 49, (July, 1953). (8) Manly, R. S., and Bibby, B. G., •. Dent. Res., :18, 160 (1949). (9) Bruckner, R. J., Hill, T. J., and Wollpert, B. J., Ibid., 31, 105 (1952). (10) Manly, R. S., and Hargreaves, G., Presented at the International Association for Dental Research, French Lick, Ind., March 21, 1954. (11) Fosdick, L. S., Calandra, J. C., Blackwell, R. Q., and Burrill, J. H., 5 e. Dent. Res., 32, 486 (1953). (12) Stepban• R. M, and Miller• B. F.• Ibid., 22, 53 (1943).
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276 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS TaBt, E 4 (Continued) Tetradecylamine .................................................. s/10 Tetraethylene pentamine ........................................... 1.0 1,2,3,4-Tetrahydrocarbazole ........................................ s/10 N,N'-Tetrahydroxypropyl ethylene diamine .......................... 0.1 1-Phenyl-5~[1-methylamine-ethyl] tetrazole ........................... 0.1 Triallyl cyanurate ................................................. s/10 2,4,6-Tri (di(2-ethylhexyl) aminomethyl) phenol ....................... s/2 pg 2,4,6-Tri (dimethylaminomethyl) phenol ............................. 1.0 pg Recoveries over 100 per cent Alkyl pyridines HB ............................................... s/10 2-Amino-2-methyl-1, 3-propanediol .................................. 0.1 4-Aminophenol ................................................... 0.1 P-Aminophenyl phosphoric acid ..................................... s/10 3-Amino-propanol ................................................. 0.1 2-Aminopyridine .................................................. s/10 Amyl cyclohexyl ammonium oleate .................................. 0.1 1-(0-Anisyl)-3-diethylamino-2-propanol HCl .......................... 0.01 Benzylamine ...................................................... 1.0 Benzylidene quinaldine ............................................ 0.1 N-Butylamine .................................................... 0.1 4-Butyl (5 or 6) methylpiperazine ................................... 0.1 Cyclohexylaminoethanol ........................................... 0.1 1-Cyclohexylamino-2-propanol ...................................... 0.1 pg 3,5-Dicarbethoxy-2,6-dimethyl-4-propyl-l,4 dihydropyridine ............ s/10 Diethylamine ..................................................... 1.0 B-Diethylaminoethanol ............................................ 0.1 B-Diethylamino propylamine ....................................... 1.0 Diethyl N,N'-ethylene di(B-amino-crotonate) ........................ s/10 6,7-Dimethoxy-l,2,3,4-tetrahydro isoquinoline ........................ 0.02 N,N-Dimethylhexadecylamine ...................................... s/10 2,6-Dimethyl-4-octadecyl-morpholine ................................ 0.1 Di (2,5-dimethyl pyrryl) ethane ..................................... s/10 Ethanol amine .................................................... 0.1 Di (2-ethylhexyl) ethylenediamine ................................... 0.1 Dioctadecylamine ................................................. s/10 N-Diphenylmethyl, N'-ip-ethoxybenzyl piperazine ..................... s/10 2-(l-E thylamyl)-3-(2-etnylhexyl) oxazolidine .......................... s/10 Ethylenediamine q- 50 M propylene oxide q- 200 M ethylene oxide ..... 0.1 Ethylenediamine q- 100 M propylene oxide q- 100 M ethylene oxide .... 0.1 1-(2-Ethylhexyl)-2-heptadecyl glyoxalidine ........................... s/10 N-Fluorene-N'-methyl piperazine dihydrobromide ..................... 0.1 2 Hepta decyl-l-(hydroxyethyl)-l,4,5,6-tetrahydropyrimidine ........... s/10 1,6-Hexanediamine ................................................ 1.0 3,3' Iminobispropylamine .......................................... 1.0 B-Isobutylaminoethanol ........................................... 0.1 N-Isobu tyldiethanolamine .......................................... 1.0 3-Methoxypropylamine ............................................ 1.0 N-Methyldiethanolamine .......................................... 1.0 1-Methyl 2,2-di(methoxyethoxy) ethylamine .......................... s/2 pg 4,4'-(Methylene-dioxydiethyl) di-morpholine ......................... 0.1 Monocaine formate ................................................ 0.1 Monoisopropanolamine ............................................ 0.1 N,N'-Di (4-morphylpropyl)-piperazine ............................... 0.1 Nicotine sulfate solution 40% ...................................... s/10 N-Octadecyl pyrrolidine ........................................... s/10 2-Phenylbenzoxazole .............................................. 0.1 Phenyl biguanide hydrochloride ..................................... 0.1 N-Phenyl-N'-methylpiperazine maleic acid salt ....................... 0.1 4-Phenylsemicarbazide HCl ......................................... s/10 Rosin amine D plus two moles ethylene oxide ........................ s/2 Tallow amine ..................................................... s/10 N,N,N',N'-Tetra butylmethylene diamine ........................... 1.0 Triisopropanol amine ........................................... 0.1
ENZYME INHIBITORS FOR DENTIFRICES 277 rapidity of penetration should be tested for their duration of action beyond the one-hour period which is the safe limit of extrapolation from the primary screening method. Inhibitors for use in dentifrice should have an action which lasts for twelve hours, the usual interval between the customary morning and evening brushing, and inhibition can be studied for twelve hours with the procedure we have described. With these two screening principles the ten most active compounds could be selected from the original hundred. The ten would certainly deserve initial study of toxicity. Any toxic substance could be replaced by com- pounds that rank next highest by in vitro tests, then the ten could be studied without undue cost by means of plaque pH drop tests used by Stephan (12) and others. The ten compounds might also be used for evaluation on dental caries activity with hamsters or rats. The best of the ten could be selected for clinical trial on the basis of a wide variety of data on inhibitory action. SUMMARY The aims, scope, and methods of an Inhibitor Survey Program have been described, and some background has been presented regarding the assump- tions that dental investigators make in their search for inhibitors for denti- frice use. Examples have been given of the findings with amines. Twenty active amines were selected from a group of 156 tested. Compounds ca- pable of inhibiting acid production were generally alkylated amines, ethylene diamines, imidazolines, or piperazines. It is recommended that these and other chemicals be examined next for their effectiveness during short contact with a synthetic dental plaque, and for the duration of their action. The substances which show rapid penetra- tion and good retention deserve to be investigated by toxicity and other in vivo studies. This approach is suggested as an efficient means of selecting one compound from a large group of substances that appear promising from primary screening methods. REYERENC•S (1) Fosdick, L. S., •. Am. Dent. Assoc., 40, 133 (1950). (2) Zander, H. A., Ibid., 40, 569 (1950). (3) Hill, T. J., Rasch, C., and Wollpert, B., •7. Dent. Res., 32, 453 (1953). (4) Stephan, R. M., Ibid., 22, 63 (1943). (5) Bibby, B. G., Ibid., 24, 297 (1945). (6) Muhler, J. C., Nebergall, W. H., and Day, H. G., Ibid., 33, 33 (1954). (7) Nevin, R. B., Walsh, J.P., and King, R. M., N. Z. Dent. 7., 49, (July, 1953). (8) Manly, R. S., and Bibby, B. G., •. Dent. Res., :18, 160 (1949). (9) Bruckner, R. J., Hill, T. J., and Wollpert, B. J., Ibid., 31, 105 (1952). (10) Manly, R. S., and Hargreaves, G., Presented at the International Association for Dental Research, French Lick, Ind., March 21, 1954. (11) Fosdick, L. S., Calandra, J. C., Blackwell, R. Q., and Burrill, J. H., 5 e. Dent. Res., 32, 486 (1953). (12) Stepban• R. M, and Miller• B. F.• Ibid., 22, 53 (1943).

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