Discovery of melanin-concentrating hormone receptor R1 antagonists using high-throughput synthesis.

A structure-activity study on benzylpiperidine 1 was accomplished by utilizing high-throughput synthesis. Three focused libraries were designed and synthesized to quickly develop SAR. Further optimization led to the discovery of compound 2, an MCH receptor R1 antagonist with over 400-fold improvement in biological activity over the original lead.

[1]  W. Greenlee,et al.  Synthesis, SAR, and biological evaluation of oximino-piperidino-piperidine amides. 1. Orally bioavailable CCR5 receptor antagonists with potent anti-HIV activity. , 2002, Journal of medicinal chemistry.

[2]  M. Miller,et al.  Concise formation of 4-benzyl piperidines and related derivatives using a Suzuki protocol. , 2001, The Journal of organic chemistry.

[3]  S. Gammeltoft,et al.  A role for melanin-concentrating hormone in the central regulation of feeding behaviour , 1996, Nature.

[4]  A. Carpenter,et al.  Melanin-concentrating hormone receptor antagonists as potential antiobesity agents , 2002 .

[5]  T. Willson,et al.  AMEBA: An acid sensitive aldehyde resin for solid phase synthesis , 1997 .

[6]  J. Flippen-Anderson,et al.  Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist. , 1994, Journal of medicinal chemistry.

[7]  H. Kawauchi,et al.  Characterization of melanin-concentrating hormone in chum salmon pituitaries , 1983, Nature.

[8]  B. Lowell,et al.  Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. , 2001, The Journal of clinical investigation.

[9]  J. Chambers,et al.  Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1 , 1999, Nature.

[10]  Mark D. McBriar,et al.  Therapeutic potential of melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity , 2004, Expert opinion on investigational drugs.

[11]  Yuji Ishihara,et al.  T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist. , 2002, European journal of pharmacology.

[12]  B. Lowell,et al.  Mice lacking melanin-concentrating hormone are hypophagic and lean , 1998, Nature.

[13]  M. Bednarek,et al.  Synthesis and biological evaluation in vitro of selective, high affinity peptide antagonists of human melanin-concentrating hormone action at human melanin-concentrating hormone receptor 1. , 2002, Biochemistry.

[14]  Trond Ulven,et al.  4-Acylamino-and 4-ureidobenzamides as melanin-concentrating hormone (MCH) receptor 1 antagonists. , 2004, Bioorganic & medicinal chemistry letters.

[15]  T. Kowalski,et al.  Melanin-concentrating hormone-1 receptor antagonism decreases feeding by reducing meal size. , 2004, European journal of pharmacology.

[16]  C. L. Chaffer,et al.  The Feeding Response to Melanin-Concentrating Hormone Is Attenuated by Antagonism of the NPY Y1-Receptor in the Rat. , 2002, Endocrinology.

[17]  Ju Gao,et al.  Synthesis and evaluation of 2-amino-8-alkoxy quinolines as MCHr1 antagonists. Part 2. , 2004, Bioorganic & medicinal chemistry letters.

[18]  T. Miyoshi,et al.  Printed in U.S.A. Copyright © 1997 by The Endocrine Society Melanin-Concentrating Hormone Acutely Stimulates Feeding, But Chronic Administration Has No Effect on , 2022 .

[19]  Yumiko Saito,et al.  Molecular characterization of the melanin-concentrating-hormone receptor , 1999, Nature.

[20]  Peter Lockey,et al.  Structure-activity relationships of a novel series of melanin-concentrating hormone (MCH) receptor antagonists. , 2004, Bioorganic & medicinal chemistry letters.