T-type calcium channel blockers: Spiro-piperidine azetidines and azetidinones - Optimization, design and synthesis

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 15, 2010, Pages 4602-4606

  Smith, Elizabeth M ^a   Sorota, Steve ^a   Kim, Hyunjin M ^a   McKittrick, Brian A ^a   Nechuta, Terry L ^a   Bennett, Chad ^a   Knutson, Chad ^a   Burnett, Duane A ^a   Kieselgof, Jane ^a   Tan, Zheng ^a   Rindgen, Diane ^a   Bridal, Terry ^a   Zhou, Xiaoping ^a   Jia, Yu Ping ^a   Dong, Zoe ^a   Mullins, Debbie ^a   Zhang, Xiaoping ^a   Priestley, Tony ^a   Correll, Craig C ^a   Tulshian, Deen ^a   Czarniecki, Michael ^a   Greenlee, William J ^a   more..

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

Neuropathic pain; Spiro azetidines; Spiro azetidinones; T type calcium channel (Ca V3.2)

Indexed keywords

ANALGESIC AGENT; AZETIDINE DERIVATIVE; AZETIDINONE DERIVATIVE; CALCIUM CHANNEL BLOCKING AGENT; CALCIUM CHANNEL T TYPE; PIPERIDINE DERIVATIVE; VANILLOID RECEPTOR 1; VOLTAGE GATED CALCIUM CHANNEL;

ANIMAL EXPERIMENT; AREA UNDER THE CURVE; ARTICLE; DRUG METABOLISM; DRUG POTENCY; DRUG PROTEIN BINDING; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; INFLAMMATION; NEUROPATHIC PAIN; NONHUMAN; RAT; STRUCTURE ACTIVITY RELATION;

ANIMALS; AZETIDINES; CALCIUM CHANNEL BLOCKERS; CALCIUM CHANNELS, T-TYPE; DRUG DESIGN; HUMANS; PAIN; PIPERIDINES; PROTEIN BINDING; RATS; SPIRO COMPOUNDS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77955415074     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.06.012     Document Type: Article

References (21)

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10. IonWorks Screen for hCaV3.2.
11. Manual Whole Cell Patch Clamp experimental, see Supplementary data.
12. TRPV1 assay.
13. Mouse TRPV1: NL version experimental, see Supplementary data.
14. DMPK for compounds 2, 3, and 4.
15. S.B. Rosenblum, T. Huynh, A. Afonso, H.R. Davis, N. Yumube, J.W. Clader, and D.A. Burnett J. Med. Chem. 41 1988 973
16. For example, 2 refers to racemic mixture; 2a refers to isomer A, faster eluting; and 2b refers to isomer B.
17. Procedure for preparation of compounds 20 and 21.
18. 50: isomer A, 125 nM; isomer B, 1626 nM.
19. Rat spinal nerve ligation model experimental, see Supplementary data.
20. Preparation of tert-butyl 2-(5-chloropyridin-3-yl)-1-oxo-3-(pyridin-2-yl) -2,7-diazaspiro[3.5]nonane-7-carboxylate, see Supplementary data.
21. Preparation of 2-(3-chloro-4-fluorophenyl)-3-(pyridin-2-yl)-2,7- diazaspiro[3.5]nonan-1-one experimental, see Supplementary data.