Dong Ok

Structure-activity relationships in the amino acid sidechain of L-692,429

Abstract Development of L-692,429, the prototype compound of a novel class of growth hormone (GH) secretagogues1, focused on defining the structure-activity relationships in the amino acid sidechain. Modification of the dimethyl-β-alanine group revealed the basic amine as an essential pharmacophore for GH releasing activity. Evaluation of a variety of amino-substittued derivatives led to the identification of analogs with improved potency.

Discovery of the Development Candidate N-tert-Butyl Nodulisporamide: A Safe and Efficacious Once Monthly Oral Agent for the Control of Fleas and Ticks on Companion Animals

Nodulisporic acid A (1) is a structurally complex fungal metabolite that exhibits systemic efficacy against fleas via modulation of an invertebrate specific glutamate-gated ion channel. In order to identify a nodulisporamide suitable for monthly oral dosing in dogs, a library of 335 nodulisporamides was examined in an artificial flea feeding system for intrinsic systemic potency as well as in a mouse/bedbug assay for systemic efficacy and safety. A cohort of 66 nodulisporamides were selected for evaluation in a dog/flea model; pharmacokinetic analysis correlated plasma levels with flea efficacy. These efforts resulted in the identification of the development candidate N-tert-butyl nodulisporamide (3) as a potent and efficacious once monthly oral agent for the control of fleas and ticks on dogs and cats which was directly compared to the topical agents fipronil and imidacloprid, with favorable results obtained. Multidose studies over 3 months confirmed the in vivo ectoparasiticidal efficacy and established that 3 lacked overt mammalian toxicity. Tissue distribution studies in mice using [(14)C]-labeled 3 indicate that adipose beds serve as ligand depots, contributing to the long terminal half-lives of these compounds.

Structure-activity relationships of the non-peptidyl growth hormone secretagogue L-692,429

Abstract Systematic investigation of the amino acid sidechain of L-692,429, the prototype of a novel class of benzolactam growth hormone (GH) secretagogues, has led to the preparation of L-692,585, a 2(R)-hydroxypropyl amino analog, which is twenty times more potent in vitro than L-692,429. Additional amino modifications reported here further define the structure-activity profile for L-692,429.

Improved syntheses of fluorinated tertiary butylamines

Abstract Two new and efficient methods using cyclic sulfamidate and nitrone chemistry were developed for the synthesis of the sterically congested 1,1-dimethyl-2-fluoroethylamine ( 1 ), 2-fluoro-1-(fluoromethyl)-1-methyl-ethylamine ( 2 ) and 2-fluoro-1,1-bis-(fluoromethyl)-ethylamine ( 3 ).

Benzolactam growth hormone secretagogues: replacements for the 2′-tetrazole moiety of L-692,429

Abstract A variety of 2′-biphenyl substituents was investigated as replacements for the 2′-tetrazole moiety of the non-peptidyl growth hormone secretagogue L-692,429. The 2′-carboxamide 22 and N-2-hydroxypropyl tetrazoles 7a,b were identified as neutral pharmacophores with similar potency to that of the acidic 2′-tetrazole. N-Alkyl tetrazoles, sulfonamides and N-acyl sulfonamides were generally less potent 2′-replacements.