A potent, orally bioavailable benzazepinone growth hormone secretagogue

  • J Med Chem. 1998 May 7;41(10):1716-28. doi: 10.1021/jm970816j.
R J DeVita  1 ,  R Bochis ,  A J Frontier ,  A Kotliar ,  M H Fisher ,  W R Schoen ,  M J Wyvratt ,  K Cheng ,  W W Chan ,  B Butler ,  T M Jacks ,  G J Hickey ,  K D Schleim ,  K Leung ,  Z Chen ,  S L Chiu ,  W P Feeney ,  P K Cunningham ,  R G Smith
Affiliations
  • 1. Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065-0900, USA.
PMID: 9572898 DOI: 10.1021/jm970816j
Abstract

The identification of L-739,943 (8b), a potent, orally bioavailable benzolactam growth hormone secretagogue, is obtained from zwitterionic L-692,429 through modification of its amino acid side chain and replacement of the acidic 2'-tetrazole with the neutral and potency enhancing 2'-(N-methylaminocarbonylamino)methyl substituent. L-739,943 is orally active for the release of growth hormone in beagle dogs at doses as low as 0.5 mg/kg. Oral bioavailability in dogs of 8b is 24% at a dose of 2 mg/kg with a mean drug Cmax of 145 +/- 46 ng/mL. L-739,943 represents a significant breakthrough in terms of both potency and oral bioavailability as compared to the prototype benzolactam L-692,429.

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