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Miguel A. Ondetti

  • Born: May 14, 1930, Buenos Aires, Argentina
  • Died: August 23, 2004

  Interview Details

Interview no.: 0126
Interview Date: January 12, 1995
Location: Princeton, New Jersey
Interviewer: James J. Bohning
No. of pages: 58
Sponsor: Society of Chemical Industry
Society of Chemical Industry

  Abstract of Interview

Miguel A. Ondetti begins this interview by describing his parents' immigrant background and work in Argentina, his early interests in chemistry, and his education at vocational school in Buenos Aires. Upon high school graduation, Ondetti began work as a bookkeeper, continuing studies at night to meet university entrance requirements. He began chemistry coursework at the University of Buenos Aires while supporting himself with accounting work for the government. Here, he describes his broad training in chemistry, Argentina's political climate, and his Ph.D. scholarship and carbohydrates research for V. Deulofeu at The Squibb Institute. Upon graduation in 1957, Ondetti explored other opportunities before accepting a position with Squibb's alkaloid isolation group, where he remained until 1960, when after much consideration he accepted a job with Squibb, New Jersey. In New Jersey, Ondetti worked in the peptide chemistry group, synthesizing the nonapeptide bradykinin under M. Bodanszky, with whom he co-wrote Peptide Synthesis. He discusses adjusting to life and work in the U.S. and his advancement in the peptide synthesis field and promotion to group head when Bodanszky pursued a career in academia. Ondetti was part of a group effort to synthesize gastrointestinal hormones, particularly secretin, a peptide amide that stimulates the pancreas to secrete bicarbonate and water. While Bodanszky pursued stepwise synthesis of the peptide, Ondetti worked with E. Sabo on fragment condensation. Both approaches eventually led to fully active synthetic secretin; the fragment condensation approach was used to obtain synthetic secretin for clinical studies, the results of which discouraged further development. Next, Ondetti worked with Sabo to synthesize cholecystokinin, which stimulates contraction of the gall bladder and secretion of enzymes from the pancreas. Here he describes problems with the synthetic peptide's development and its eventual use as a diagnostic agent. Also discussed is the importance of his relationships with Sabo and Z. Horovitz. In 1967, A. D. Welch became Squibb's president, and changes in company research agendas led Ondetti to work on peptidase inhibitors. Ondetti describes acquiring venom for isolation of enzyme inhibitors, isolating angiotensin converting enzyme inhibitors, and learning to isolate and sequence peptides in competition with researchers at Brookhaven National Laboratories. In 1973, for practical reasons, Squibb's angiotensin converting enzyme (ACE) inhibitor work officially ended, but Ondetti's interest in the subject continued. Prompted by discoveries of L. D. Byers and R. Wolfenden and interactions with D. Cushman, Ondetti decided to pursue synthesis of succinyl-L-proline, which was found to potentiate the contractile activity of bradykinin. Continuing work in this direction, Ondetti and Sabo started making hydroxamic acids with better activity and eventually sulfhydryl compounds with great activity. After continued research, this work evolved into captopril. Here, Ondetti describes human trials of this drug, problems with FDA approval, the effectiveness of captopril for hypertension treatment, and follow-up research leading to new therapeutic agents. The interview closes with Ondetti's reflections on the fields of chemistry and pharmaceutical research, and his own career; highlighted are notions of success and rewards, collaboration between industry and academia, rational drug design, and leadership.

  Education

1955 Licentiate, Chemistry, University of Buenos Aires
1957 Ph.D., Organic Chemistry, University of Buenos Aires

  Professional Experience

Department of Energy, Argentina Government

1948 - 1957 Bookkeeper

University of Buenos Aires

1957 - 1960 Instructor

Catholic Institute for Teachers

1957 - 1960 Professor

The Squibb Institute for Medical Research, Argentina

1957 - 1960 Senior Research Chemist

The Squibb Institute for Medical Research, New Jersey

1960 - 1966 Senior Research Chemist

The Squibb Institute for Medical Research, New Jersey

1966 - 1973 Research Group Leader, Peptide Synthesis

The Squibb Institute for Medical Research, New Jersey

1973 - 1976 Section Head, Peptides, Steroids, and Antibiotic Research

The Squibb Institute for Medical Research, New Jersey

1976 - 1980 Director, Department of Biological Chemistry

The Squibb Institute for Medical Research, New Jersey

1980 - 1981 Associate Director, Chemical and Microbiological Research

The Squibb Institute for Medical Research, New Jersey

1981 - 1983 Vice President, Basic Research

The Squibb Institute for Medical Research, New Jersey

1984 - 1989 Vice President of Research, Cardiopulmonary Diseases

The Squibb Institute for Medical Research, New Jersey

1989 - 1990 Senior Vice President of Research, Cardiovascular Diseases

The Squibb Institute for Medical Research, New Jersey

1990 - 1991 Senior Vice President, Cardiovascular and Metabolic Diseases

The Squibb Institute for Medical Research, New Jersey

1991 Retired

  Honors

1981 Alfred Burger Award in Medicinal Chemistry, American Chemical Society
1983 Thomas Alva Edison Patent Award, Research and Development Council, New Jersey
1983 Ciba Award for Hypertension Research, American Heart Association, Council on High Blood Pressure Research
1986 Chairmanís Edward Robinson Squibb Award, E. R. Squibb & Sons, Inc.
1988 Award for Contributions to Medical Science, Pharmaceutical Manufacturers Association and National Health Council
1988 Inventor of the Year Award, New Jersey Inventors Congress
1991 Perkin Medal, Society of Chemical Industry (American Section)
1991 Warren Alpert Foundation Prize, Harvard Medical School
1992 Award for Creative Invention, American Chemical Society
1992 Herman Bloch Award for Scientific Excellence in Industry, University of Chicago

  Table of Contents

Title and Description Page

Family Background and Early Education in Argentina 1

Parents' Italian and immigrant backgrounds. Father's work as craftsman and night watchman in Buenos Aires. Early Argentinean education in vocational school for bookkeeping/accounting. Early accounting work and night school to prepare for university education in chemistry.

University Education 3

Supporting self through accounting work at Argentina's Department of Energy. Interests in biology and chemistry. Curriculum and broad scientific training at the University of Buenos Aires. Ph.D. scholarship through The Squibb Institute. Political and social climate in Argentina and its effects on educational system and Squibb. Research with V. Deulofeu on carbohydrates. Relationship with Deulofeu.

Early Career at The Squibb Institute for Medical Research, Argentina 6

Accepting job in 1957. Work 1957 to 1960, looking for new alkaloids. Offer to work for Squibb, New Jersey, United States. Social factors influencing decision to decline British Council scholarship in favor of U.S. job.

Early Work at The Squibb Institute for Medical Research, New Jersey 8

Salary and social and language adjustments in the U.S. Peptide chemistry group. Differences in lab work in Argentina vs. U.S. and peptides vs. other chemistry. Interactions with biologists. Relations with group head M. Bodanszky and co-authoring Peptide Synthesis. Advancing in peptide synthesis field. Promotion to group head as Bodanszky departs for academic career. Adjusting to U.S. and decision to reject 1969 offer to teach at University of Buenos Aires. Changes in pharmaceutical industry, work environment, and peptide field across career. Contributions of S. Lande and B. Merrifield to peptide field and solid phase synthesis. First work synthesizing a nonapeptide. Company support for publishing.

Later Work at Squibb 18

Origins of mid-1960s position in gastrointestinal hormone group and association with E. F. Sabo. Work on secretin synthesis with Sabo and Bodanszky. Step-wise and fragment condensation approaches. E. Sabo's background and importance. Work to synthesize and develop synthetic cholecystokinin hormone that induces the gallbladder to contract, and problems developing formulation. Importance of Z. Horovitz and internal support for ideas.

Work on Captopril 26

Changes in Squibb research agenda, 1967, as A. D. Welch becomes president. Origins of interest in peptidase inhibitors and natural products research. Acquiring venom for isolation of enzyme inhibitors. Isolating phospholipase inhibitor. Learning to isolate and sequence peptides in competition with L. Greene and S. Ferreira at Brookhaven National Laboratories. Reasons for official end and unofficial continuation of angiotensin converting enzyme (ACE) work. Interactions with D. Cushman, paper by L. D. Byers and R. Wolfenden, and work to make new type of ACE inhibitor. Problems with oral absorption. Synthesis of sulfhydryl compound and increase in activity. Internal conflicts regarding publication of captopril discovery. Human studies in Lausanne, Switzerland, and related publications. Reaction and competition from Merck. Follow-up research. Formation of captopril task force and captopril analog work. Clinical study problems, FDA restrictive use approval in 1982. New human studies and FDA unrestricted use approval, 1984. Phosphorous-containing ACE inhibitor approval.

Reflections on Chemistry Research and Career 39

Promotions through research management. Discussion of successful researchers vs. successful managers, and related financial rewards. Promotion to associate director and end of in-lab work. U.S. vs. German patent system. Need for collaboration between biologists and chemists, and influence of organizational structures. Interactions between industrial and academic research. Academics as sources of new ideas. Rational drug design. Role of computational chemistry in drug design. Industry-wide changes in R&D and emphasis on cellular and molecular targets. Meaning of winning Perkin Medal and of being a chemist. Dedication of Squibb's M. A. Ondetti Laboratories, and feelings about leadership.

Notes 51

Index 53

  About the Interviewer

James J. Bohning

James J. Bohning is professor emeritus of chemistry at Wilkes University, where he was a faculty member from 1959 to 1990. He served there as chemistry department chair from 1970 to 1986 and environmental science department chair from 1987 to 1990. Bohning was chair of the American Chemical Society’s Division of the History of Chemistry in 1986; he received the division’s Outstanding Paper Award in 1989 and has presented more than forty papers at national meetings of the society. Bohning was on the advisory committee of the society’s National Historic Chemical Landmarks Program from its inception in 1992 through 2001 and is currently a consultant to the committee. He developed the oral history program of the Chemical Heritage Foundation, and he was the foundation’s director of oral history from 1990 to 1995. From 1995 to 1998, Bohning was a science writer for the News Service group of the American Chemical Society. He is currently a visiting research scientist and CESAR Fellow at Lehigh University. In May 2005, he received the Joseph Priestley Service Award from the Susquehanna Valley Section of the American Chemical Society.

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