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Chapter 1 Recent Advances in Corticotropin-Releasing Factor Receptor Antagonists

2008; Elsevier BV; Linguagem: Inglês

10.1016/s0065-7743(08)00001-8

1557-8437

Carolyn D. Dzierba, Richard A. Hartz, Joanne J. Bronson,

Tryptophan and brain disorders

Corticotropin releasing factor (CRF), a 41 amino acid peptide is considered to be one of the principal regulators of the hypothalamic–pituitary–adrenal (HPA) axis, which coordinates the endocrine, behavioral, and autonomic responses to stress. CRF mediates its action through binding to two well-characterized, class B subtype G-protein coupled receptors, CRF-R1 and CRF-R2. CRF-R1 has been the most extensively studied CRF receptor as a potential therapeutic target, with both preclinical and clinical studies suggesting that antagonists of CRF-R1 may offer promise in treatment of stress-related disorders. This chapter covers advances in the discovery and development of CRF-R1 antagonists. The classes of CRF-R1 antagonists have some key features: (1) an aromatic heterocyclic core that includes an sp2 nitrogen acting as a hydrogen bond acceptor; (2) an aryl ring in an orthogonal orientation to the core ring, which is minimally substituted in the ortho- and para-positions; (3) a halide or small alkyl group ortho to the sp2 nitrogen of the heterocyclic core; and (4) a branched, lipophilic group, with limited tolerance for polar functional groups, para to the sp2 nitrogen of the heterocyclic core. Many potent, small molecule CRF-R1 antagonists from a variety of chemical classes have been reported since the disclosure of CRF-R1 antagonist CP-154,526.