Enhancement of pharmacokinetic properties and in vivo efficacy of benzylidene ketal M2 muscarinic receptor antagonists via benzamide modification

Bioorganic and Medicinal Chemistry Letters

Volumn 12, Issue 23, 2002, Pages 3479-3482

  Boyle, Craig D ^a   Vice, Susan F ^a   Campion, Jennifer ^a   Chackalamannil, Samuel ^a   Lankin, Claire M ^a   McCombie, Stuart W ^a   Billard, William ^a   Binch, Iii, Herbert ^a   Crosby, Gordon ^a   Williams, Mary Cohen ^a   Coffin, Vicki L ^a   Cox, Kathleen A ^a   Grotz, Diane E ^a   Duffy, Ruth A ^a   Ruperto, Vilma ^a   Lachowicz, Jean E ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZYLIDENE DERIVATIVE; MUSCARINIC M2 RECEPTOR ANTAGONIST; ACETYLCHOLINE; BENZAMIDE DERIVATIVE; MUSCARINIC RECEPTOR; MUSCARINIC RECEPTOR BLOCKING AGENT;

ARTICLE; CHEMICAL MODIFICATION; DRUG BIOAVAILABILITY; DRUG EFFICACY; DRUG SELECTIVITY; IN VIVO STUDY; RECEPTOR AFFINITY; ANIMAL; AREA UNDER THE CURVE; BIOSYNTHESIS; CHEMISTRY; DRUG DESIGN; DRUG EFFECT; DRUG SCREENING; HUMAN; LIVER MICROSOME; METABOLISM; MICRODIALYSIS; RAT; STRUCTURE ACTIVITY RELATION;

ACETYLCHOLINE; ANIMALS; AREA UNDER CURVE; BENZAMIDES; BENZYLIDENE COMPOUNDS; DRUG DESIGN; DRUG EVALUATION, PRECLINICAL; HUMANS; MICRODIALYSIS; MICROSOMES, LIVER; MUSCARINIC ANTAGONISTS; RATS; RECEPTORS, MUSCARINIC; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 18644386131     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(02)00742-4     Document Type: Article

References (21)

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12. See the following reference for previous ketal SAR studies and syntheses: Boyle C.D., Chackalamannil S., Chen L.-Y., Dugar S., Pushpavanam P., Billard W., Binch H. III, Crosby G., Cohen-Williams M., Coffin V.L., Duffy R.A., Ruperto V., Lachowicz J.E. Bioorg. Med. Chem. Lett. 10:2000;2727.
13. See ref 6 for the methodology used to obtain muscarinic receptor binding data. The data presented is the mean of duplicate values (SEM <15%). All determinations were performed at least twice.
14. Procedure described in: Hecht S., Chen C., Hoffmann D. Cancer Res. 38:1978;215. Compounds (10 μg/mL concentration) were incubated in human microsomes and their metabolic stability was determined by the percent of the parent compound remaining after 20 min. The stability was compared to that observed for SCH 72788 (Lachowicz, J. E.; Duffy, R. A.; Ruperto, V.; Kozlowski, J.; Zhou, G.; Clader, J.; Billard, W.; Binch, H., III; Crosby, G.; Cohen-Williams, M.; Strader, C. D.; Coffin, V. Life Sci. 2001, 68, 2585), which was used as a reference incubated at the same time under the same conditions. A difference of 30% was considered significant and compounds that showed stabilities 30% more than SCH 72788 were considered further. SCH 72788 typically had 15-30% parent remaining after 20 min.
15. 2 activity: Cox, K. Unpublished results.
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18. ClogP values were calculated using SYBYL version 6.6 accessed via the ClogP column type and various expression generators with a special license (Biobyte) available from Tripos, Inc.
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21. Bioavailability of naphthamide 1: rat=44%, c. monkey=9%. Bioavailability of anthranilamide 18: rat=80%, c. monkey=15%.