Synthesis and structure-activity relationships of spirohydantoin-derived small-molecule antagonists of the melanin-concentrating hormone receptor-1 (MCH-R1)

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 8, 2007, Pages 2171-2178

  Rowbottom, Martin W ^a   Vickers, Troy D ^a   Tamiya, Junko ^a   Zhang, Mingzhu ^a   Dyck, Brian ^a   Grey, Jonathan ^a   Schwarz, David ^a   Heise, Christopher E ^a   Hedrick, Michael ^a   Wen, Jenny ^a   Tang, Hui ^a   Wang, Hua ^a   Fisher, Andrew ^a   Aparicio, Anna ^a   Saunders, John ^a   Goodfellow, Val S ^a  

^a NEUROCRINE BIOSCIENCES INC   (United States)

Author keywords

CYP3A4; MCH; MCH antagonists; MCH R1; Melanin concentrating hormone receptor 1 antagonists; Obesity; Spirohydantion

Indexed keywords

MELANIN CONCENTRATING HORMONE; MELANIN CONCENTRATING HORMONE RECEPTOR 1; PEPTIDE HORMONE RECEPTOR BLOCKING AGENT; SMALL MOLECULE MELANIN CONCENTRATING HORMONE RECEPTOR 1 BLOCKING AGENT; UNCLASSIFIED DRUG;

ARTICLE; BINDING AFFINITY; DRUG ACTIVITY; DRUG BINDING; DRUG BIOAVAILABILITY; DRUG DESIGN; DRUG POTENCY; DRUG SYNTHESIS; NONHUMAN; STRUCTURE ACTIVITY RELATION;

ANTI-OBESITY AGENTS; DRUG DESIGN; HUMANS; HYDANTOINS; KINETICS; PROTEIN BINDING; RECEPTORS, PITUITARY HORMONE; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33947591478     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2007.01.104     Document Type: Article

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18. i values were highly reproducible with an average standard error of the mean of less than 45% for replicate determinations.
19. 50 values were highly reproducible with an average standard error of the mean of less than 45% for replicate determinations.
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21. Inhibition assays were carried out using microsomes isolated from transfected cells expressing only CYP3A4, and in the presence of the fluorescent substrate BFC. Ketoconazole was used as a positive control.
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25. 0-24h was determined to be 2796 ng h/mL. All data were determined in male Sprague-Dawley rats (n = 3).
26. Compound 19 was prepared in four steps from 4-piperidone hydrochloride (14) using a similar procedure outlined for 17 (Table 3).