Projects per year
Abstract
The calcium-sensing receptor (CaSR) is a clinical target in the treatment of hyperparathyroidism and related diseases. However, clinical use of approved CaSR-targeting drugs such as cinacalcet is limited due to adverse side effects including hypocalcaemia, nausea and vomiting, and in some instances, a lack of efficacy. The CaSR agonist and positive allosteric modulator (ago-PAM), AC265347, is chemically distinct from clinically-approved CaSR PAMs. AC265347 potently suppressed parathyroid hormone (PTH) release in rats with a lower propensity to cause hypocalcaemia compared to cinacalcet and may therefore offer benefits over current CaSR PAMs. Here we report a structure activity relationship (SAR) study seeking to optimise AC265347 as a drug candidate and disclose the discovery of AC265347-like compounds with diverse pharmacology and improved physicochemical and drug-like properties.
Original language | English |
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Pages (from-to) | 3451-3462 |
Number of pages | 12 |
Journal | ChemMedChem |
Volume | 16 |
Issue number | 22 |
DOIs | |
Publication status | Published - 19 Nov 2021 |
Keywords
- AC265347
- calcium-sensing receptor
- class C GPCR
- positive allosteric modulators
- structure-activity relationship
Projects
- 4 Finished
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Towards the rational design of calcium sensing receptor allosteric modulators for the treatment of osteoporosis and calcium handling disorders
Leach, K., Gregory, K., Conigrave, A., Capuano, B., Kufareva, I., Thakker, R. & Hannan, F. M.
National Health and Medical Research Council (NHMRC) (Australia)
1/01/18 → 31/12/21
Project: Research
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Exploring metabotropic glutamate receptor 5 bias, allostery and heteromers
1/07/17 → 30/12/21
Project: Research
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Understanding bias and allostery at the calcium sensing receptor
Leach, K.
Australian Research Council (ARC), Monash University
1/01/17 → 22/07/22
Project: Research