Investigation of (oxodioxolenyl)methyl carbamates as nonchiral bioreversible prodrug moieties for chiral amines

Journal of Medicinal Chemistry

Volumn 39, Issue 2, 1996, Pages 480-486

  Alexander, Jose ^a,b   Bindra, Dilbir S ^a,c   Glass, Joan D ^a   Holahan, Marie A ^a   Renyer, Mara L ^a   Rork, Gerald S ^a   Sitko, Gary R ^a   Stranieri, Maria T ^a   Stupienski, Raymond F ^a   Veerapanane, Hemalata ^a   Cook, Jacquelynn J ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b Pharmacology ^*  (United States)

^c DUPONT COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

4 [[(3',4' DIMETHOXYPHENETHYL)CARBAMOYL]METHYL] 5 METHYL 1,3 DIOXOL 4 EN 2 ONE; 4 [[(3,4 DIMETHOXYPHENETHYL)CARBAMOYL]METHYL] 5 PHENYL 1,3 DIOXOL 4 EN 2 ONE; ADRENALIN; AMINE; CARBAMIC ACID DERIVATIVE; COLLAGEN; FIBRINOGEN RECEPTOR ANTAGONIST; L 734217; UNCLASSIFIED DRUG;

ANIMAL EXPERIMENT; ARTICLE; CHIRALITY; CONTROLLED STUDY; DOG; DRUG BIOAVAILABILITY; DRUG HALF LIFE; DRUG HYDROLYSIS; DRUG RESEARCH; DRUG SCREENING; DRUG SYNTHESIS; FEMALE; INTRAVENOUS DRUG ADMINISTRATION; MALE; NONHUMAN; ORAL DRUG ADMINISTRATION; PARTITION COEFFICIENT; RAT; THROMBOCYTE AGGREGATION INHIBITION;

AMINES; ANIMALS; BIOLOGICAL AVAILABILITY; CARBAMATES; DOGS; FEMALE; MALE; PLATELET AGGREGATION INHIBITORS; PRODRUGS; RATS; STEREOISOMERISM;

EID: 13344275868     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm9506175     Document Type: Article

References (37)

1. For a list, see: Alexander, J.; Cargyl, R.; Michelson, R.; Schwam, H. (Acyloxy)alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through Biological Membranes. J. Med. Chem. 1988, 31, 318-322.
2. For additional methods, see: Amesberry, K. L.; Gerstenberger, A. L.; Borchart, R. T. Amine Prodrugs which Utilize Hydroxy Amide Lactonization. II. A Potential Esterase-Sensitive Amide Prodrug. Pharm. Res. 1991, 8, 455-461. Naringrekar, V. H.; Stella, J. V. Mechanism of Hydrolysis and Structure-Stability Relationship of Enaminones as Potential Prodrugs of Model Primary Amines. J. Pharm. Sci. 1990, 79, 138-146.
3. For additional methods, see: Amesberry, K. L.; Gerstenberger, A. L.; Borchart, R. T. Amine Prodrugs which Utilize Hydroxy Amide Lactonization. II. A Potential Esterase-Sensitive Amide Prodrug. Pharm. Res. 1991, 8, 455-461. Naringrekar, V. H.; Stella, J. V. Mechanism of Hydrolysis and Structure-Stability Relationship of Enaminones as Potential Prodrugs of Model Primary Amines. J. Pharm. Sci. 1990, 79, 138-146.
4. Alexander, J.; Fromtling, R. A.; Bland, J. A.; Pelak, B. A.; Gilfillan, E. C. (Acyloxy)alkyl Carbamate Prodrugs of Norfloxacin. J. Med. Chem. 1991, 34, 78-81.
5. Gogate, U. S.; Repta, A. J.; Alexander, J. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of amines. I. Kinetics and Mechanism of Degradation in Aqueous Solutions. Int. J. Pharm. 1987, 40, 235-248. Gogate, U. S.; Repta, A. J. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of Amines. II. Esterase-catalyzed Release of Parent Amines from Model Prodrugs. Int. J. Pharm. 1987, 40, 249-255.
6. Gogate, U. S.; Repta, A. J.; Alexander, J. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of amines. I. Kinetics and Mechanism of Degradation in Aqueous Solutions. Int. J. Pharm. 1987, 40, 235-248. Gogate, U. S.; Repta, A. J. N-(Acyloxyalkoxycarbonyl) Derivatives as Potential Prodrugs of Amines. II. Esterase-catalyzed Release of Parent Amines from Model Prodrugs. Int. J. Pharm. 1987, 40, 249-255.
7. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
8. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
9. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
10. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
11. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
12. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
13. Lee, V. H.; Bundgaard, H. Improved Drug Delivery with Prodrugs. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 221-297. Sloan, K. B. Functional Group Considerations in the Development of Prodrug Approaches to Solving Topical Delivery Problems. In Prodrugs; Sloan, K. B., Ed.; Marcel Dekker, Inc.: New York, 1992; pp 17-116. Bundgaard, H. Novel Chemical Approaches in Prodrug Design. Drugs Future 1991, 16, 443-458. Saulnier, M. G.; Frennesson, D. B.; Deshpande, M. S.; Hansel, S. B.; Vyas, D. M. An Efficient Method for the Synthesis of Guanidino Prodrugs. Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990. Lund, F. J.; Folkmann, M. Acyloxymethyl Carbonochloridates. New Intermediates in Prodrug Synthesis. Synthesis 1990, 1159-11166. Omar, F. A.; Farag, H. H.; Bodor, N. Synthesis and Evaluation of a Redox Chemical Delivery System for Brain-enhanced Dopamine Containing an Activated Carbamate-type Ester. J. Drug Target. 1994, 2, 309-136. Pop, E.; Wu, W.-M.; Shek, E.; Bodor, N. Chemical Delivery Systems for Drugs Containing an Amino Group: Synthesis and Properties of Some Pyridine Derivatives of Desipramine. Drug Des. Delivery 1989, 5, 93-115.
14. Safadi, M.; Olyai, R.; Stella, V. J. Phosphoryloxymethyl Carbamates and Carbonates. Novel Water-Soluble Prodrugs for Amines and Hindered Alcohols. Pharm. Res. 1993, 10, 1350-1355.
15. Moriyama, M.; Aoyama, T.; Soejima, R.; Mashimo, K. KBT-1585, A New Ampicillin Ester with Unique Pro-moiety. Abstract of Papers, 24th Interscience Conference on Antimicrobial Agents and Chemotherapeutics, Oct 8-10, Washington, DC, 1984, Abstract 125.
16. Alexander, J.; Renyer, M. L. Unpublished results
17. Ikeda, S.; Sakamoto, F.; Kondo, H.; Moriyama, M.; Tsukamoto, G. Studies on Prodrugs. III. A Convenient and Practical Preparation of Ampicillin Prodrugs. Chem. Pharm. Bull. 1984, 32, 4316-4322.
18. Miyauchi, M.; Suzuki, K.; Endo, R.; Kawamoto, I. Studies on Penem and Carbopenem. II. An Improved Synthesis of Orally Active Penem Antibiotic (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl-(5R,6S)-2-(2-Fluoroethylthio)-6-[(1R)-1- hydroxyethyl]penem-3-carboxylate. Chem. Pharm. Bull. 1990, 38, 1077-1078.
19. Saari, W. S.; Halczenko, W.; Cochran, D. W.; Dobrinska, M. R.; Vincek, W. C.; Titus, D. C.; Gaul, S. L.; Sweet, C. S. 3-Hydroxy-α-methyltyrosine Progenitors: Synthesis and Evaluation of Some (2-Oxo-1,3-dioxol-4-yl)methyl Esters. J. Med. Chem. 1984, 27, 713-717.
20. Sakamoto, F.; Ikeda, S.; Kondo, H.; Tsukamoto, G. Studies on Prodrugs. IV. Preparation and Characterization of N-(5-Substituted 2-oxo-1,3-dioxol-4-yl)methyl Norfloxacin. Chem. Pharm. Bull. 1985, 33, 4870-4877.
21. Sakamoto, F.; Ikeda, S.; Tsukamoto, G. Studies on Prodrugs. II. Preparation and Characterization of (5-Substituted 2-oxo-1,3-dioxolen-4-yl)methyl Esters of Ampicillin. Chem. Pharm. Bull. 1984, 32, 2441-2248.
22. Saito, A.; Nakashima, M. Pharmacokinetic Study of Lenampicillin (KBT-1585) in Healthy Volunteers. Antimicrob. Agents Chemother. 1986, 29, 948-950.
23. Maehara, K.; Okamoto, Y.; Kishimoto, Y.; Kitajima, H.; Uwamori, H.; Iida, Y.; Yoshioka, M.; Mase, K.; Yasunaga, K.; Ueda, Y.; Okubo, H. Clinical Studies on Lenampicillin (KBT-1585). Chemotherapy (Tokyo), 1984, 32 (Suppl. 8), 337-346.
24. Iwata, T.; Kokuba, S.; Ariga, F.; Hiramatsu, Y. The Mutagenicity of Lenampicillin Hydrochloride (KBT-1585) and its Metabolites. Chemotherapy (Tokyo) 1984, 32 (Suppl. 8), 153-160.
25. Alexander, J. Oxodioxolenylmethyl Carbamate Prodrugs for Amine Drugs. U.S. Patent 5,466,811, 1995.
26. Alexander, J.; Renyer, M. L.; Veerapanane, H. A Convenient Method for the Conversion of Halides to Alcohols. Abstract of Papers, 209th National Meeting of the American Chemical Society, Anaheim, CA, 1995; ORG. 277. Alexander, J.; Renyer, M. L.; Veerapanane, H. A Convenient Method for the Conversion of Halides to Alcohols. Synth. Commun. 1995, 25, 3875-3881.
27. Alexander, J.; Renyer, M. L.; Veerapanane, H. A Convenient Method for the Conversion of Halides to Alcohols. Abstract of Papers, 209th National Meeting of the American Chemical Society, Anaheim, CA, 1995; ORG. 277. Alexander, J.; Renyer, M. L.; Veerapanane, H. A Convenient Method for the Conversion of Halides to Alcohols. Synth. Commun. 1995, 25, 3875-3881.
28. Alpegiani, M.; Zarini, F.; Perrone, E. On the Preparation of 4-Hydroxymethyl-5-methyl-1,3-dioxol-2-one. Synth. Commun. 1992, 22, 1277-1282.
29. Breitbeil, F. W.; Wright, L.; Foss, T. H.; LaRose, R. C. Cyclic Carbonates. III. The Synthesis, Physical and Chemical Properties of Vinylene Carbonates. Trans. Ill. State Acad. Sci. 1974, 67, 139-144.
30. Brietbeil, F. W.; Skrobot, A. A. Mass Spectra and Pyrolyses of Some Vinylene Carbonates. J. Org. Chem. 1982, 47, 702-704.
31. Elphimoff-Felkin, I.; Verrier, M. Preparation and Spectral (IR and UV) Properties of Some Isomeric Pairs of α-Ketols Having or Not Having an Aryl Group Conjugated with the Carbonyl Group. Bull. Soc. Chim. Fr. 1967, 1047-1052; Chem. Abstr 1967, 67, 43523.
32. Elphimoff-Felkin, I.; Verrier, M. Preparation and Spectral (IR and UV) Properties of Some Isomeric Pairs of α-Ketols Having or Not Having an Aryl Group Conjugated with the Carbonyl Group. Bull. Soc. Chim. Fr. 1967, 1047-1052; Chem. Abstr 1967, 67, 43523.
33. Hartman, G. D., Egbertson, M. S.; Halezenko, W.; Laswell, W. L.; Duggan, M. E.; Smith, R. L.; Naylor, A. M.; Manno, P. D.; Lynch, R. J.; Zhang, G.; Chang, C. T.-C.; Gould, R. J. Non-peptide Fibrinogen Receptor Antagonists. 1. Discovery and Design of Exosite Inhibitors. J. Med. Chem. 1992, 35, 4640-4642.
34. Egbertson, M. S.; Chang, C. T.-C.; Duggan, M. E.; Gould, R. J.; Halezenko, W.; Hartman, G. D.; Laswell, W. L.; Lynch, J. J., Jr.; Lynch, R. J.; Manno, P. D.; Naylor, A. M.; Prugh, J. D.; Ramjit, D. R.; Sitko, G. R.; Smith, R. S.; Turchi, L. M.; Zhang, G. Non-peptide Fibrinogen Receptor Antagonists. 2. Optimization of Tyrosine Template as a Mimic for Arg-Gly-Asp. J. Med. Chem. 1994, 37, 2537-2551.
35. Duggan, M. E.; Naylor-Olsen, A. M.; Perkins, J. J.; Anderson, P. S.; Chang, C. T.-C.; Cook, J. J.; Gould, R. J.; Ihle, N. C.; Hartman, G. D.; Lynch, J. J.; Lynch, R. J.; Manno, P. D.; Schaffer, L. W.; Smith, R. L. Non-Peptide Fibrinogen Receptor Antagonists. 7. Design and Synthesis of a Potent, Orally Active Fibrinogen Receptor Antagonist. J. Med. Chem. 1995, 38, 3332-3341.
36. Lynch, J. J., Jr.; Cook. J. J.; Sitko, G. R.; Holahan, M. A.; Ramjit, D. R.; Mellott, M. J.; Stranden, M. T.; Stabilito, I. I.; Zhang, G.; Lynch, R. J.; Manno, P. D.; Chang, C. T.-C.; Egbertson, M. S.; Halczenko, W.; Duggan, M. E.; Laswell, W. L.; Vassallo, L. M ; Shafer, J. A.; Anderson, P. S.; Friedman, P. A.; Hartman, G. D.; Gould, R. J. Nonpeptide Glycoprotein IIb/IIIa Inhibitors. 5. Antithrombotic Effects of MK-0383. J. Pharmacol. Exp. Ther. 1995, 272, 20-32. Barrett, J. S.; Gould, R. J.; Ellis, J. D.; Holahan, M. H.; Stranieri, M. T.; Lynch, J. J., Jr.; Hartman, G. D.; Ihle, N.; Duggan, M.; Moreno, O. A.; Theoharides, A. D. Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, after Intravenous and Oral Administration in the Dog, Pharm. Res. 1994, 11, 426-431.
37. Lynch, J. J., Jr.; Cook. J. J.; Sitko, G. R.; Holahan, M. A.; Ramjit, D. R.; Mellott, M. J.; Stranden, M. T.; Stabilito, I. I.; Zhang, G.; Lynch, R. J.; Manno, P. D.; Chang, C. T.-C.; Egbertson, M. S.; Halczenko, W.; Duggan, M. E.; Laswell, W. L.; Vassallo, L. M ; Shafer, J. A.; Anderson, P. S.; Friedman, P. A.; Hartman, G. D.; Gould, R. J. Nonpeptide Glycoprotein IIb/IIIa Inhibitors. 5. Antithrombotic Effects of MK-0383. J. Pharmacol. Exp. Ther. 1995, 272, 20-32. Barrett, J. S.; Gould, R. J.; Ellis, J. D.; Holahan, M. H.; Stranieri, M. T.; Lynch, J. J., Jr.; Hartman, G. D.; Ihle, N.; Duggan, M.; Moreno, O. A.; Theoharides, A. D. Pharmacokinetics and Pharmacodynamics of L-703,014, a Potent Fibrinogen Receptor Antagonist, after Intravenous and Oral Administration in the Dog, Pharm. Res. 1994, 11, 426-431.