Potent, orally bioavailable somatostatin agonists: Good absorption achieved by urea backbone cyclization

Bioorganic and Medicinal Chemistry Letters

Volumn 9, Issue 3, 1999, Pages 491-496

  Pasternak, Alexander ^a   Pan, Yanping ^a   Marino, Dominick ^a   Sanderson, Philip E ^a   Mosley, Ralph ^a   Rohrer, Susan P ^a   Birzin, Elizabeth T ^a   Huskey, Su Er Wu ^a   Jacks, Tom ^a   Schleim, Klaus D ^a   Cheng, Kang ^a   Schaeffer, James M ^a   Patchett, Arthur A ^a   Yang, Lihu ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

L 054522; RECEPTOR SUBTYPE; SOMATOSTATIN DERIVATIVE; SOMATOSTATIN RECEPTOR; SRIF 14; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; CYCLIZATION; DOG; DRUG ABSORPTION; DRUG BIOAVAILABILITY; DRUG CLEARANCE; DRUG CONFORMATION; HYDROGEN BOND; MASS SPECTROMETRY; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ADMINISTRATION, ORAL; ANIMALS; BENZIMIDAZOLES; BIOLOGICAL AVAILABILITY; DOGS; INDOLES; SOMATOSTATIN; STRUCTURE-ACTIVITY RELATIONSHIP; UREA;

CANIS FAMILIARIS;

EID: 0033535079     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(99)00016-5     Document Type: Article

References (27)

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22. For details on the modeling of acyclic agonists as well as cyclic hexapeptide agonists see ref 4. A comparison of minimized compounds 19 and 21, overlapping the C-NCON-C urea atoms, yielded an RMS of 0.120°A. Comparisons to the cyclic hexapeptide agonist were made by visual examination.
23. Functional activities were determined either by measurement of inhibition of growth hormone release using primary cultures of rat anterior pituitary cells or by measurement of inhibition of forskolin-stimulated cAMP production in L cells stably expressing sst2 and a cAMP-responsive reporter construct, both as described in ref 4. Of the compounds reported herein, all of those evaluated in functional assays were agonists, including 21, 30, 35, and 37.
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25. Binding affinities were measured as described in ref 4. Except as noted, pharmacokinetics in beagles were calculated based on data obtained by po administration at 1 mpk and iv administration at 0.2 or 0.3 mpk in two dogs. Linear phamacokinetics were assumed.
26. i values: hSSTR-1 = 712 nM, hSSTR-2 = 3.6 nM, hSSTR-3 = 1290 nM, hSSTR-4 = 83 nM and hSSTR-5 = 584 nM.
27. Discovered in another program at Merck & Co., Inc. Its preparation will be described elsewhere.