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. 2019 Oct 15;29(20):126611.
doi: 10.1016/j.bmcl.2019.08.015. Epub 2019 Aug 9.

Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design

Alistair O'Brien  1 , Stephen P Andrews  2 , Asma H Baig  3 , Andrea Bortolato  4 , Alastair J H Brown  3 , Giles A Brown  5 , Sue H Brown  3 , John A Christopher  3 , Miles Congreve  3 , Robert M Cooke  3 , Chris De Graaf  3 , James C Errey  6 , Charlotte Fieldhouse  3 , Ali Jazayeri  5 , Fiona H Marshall  7 , Jonathan S Mason  3 , Juan Carlos Mobarec  3 , Krzysztof Okrasa  3 , Kelly N Steele  3 , Stacey M Southall  3 , Iryna Teobald  3 , Steve P Watson  3 , Malcolm Weir  3
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Identification of a novel allosteric GLP-1R antagonist HTL26119 using structure- based drug design

Alistair O'Brien et al. Bioorg Med Chem Lett. .

Abstract

A series of novel allosteric antagonists of the GLP-1 receptor (GLP-1R), exemplified by HTL26119, are described. SBDD approaches were employed to identify HTL26119, exploiting structural understanding of the allosteric binding site of the closely related Glucagon receptor (GCGR) (Jazayeri et al., 2016) and the homology relationships between GCGR and GLP-1R. The region around residue C3476.36b of the GLP-1R receptor represents a key difference from GCGR and was targeted for selectivity for GLP-1R.

Keywords: Allosteric antagonist; GCGR; GLP-1R; HTL26119.

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