2020
DOI: 10.1021/acs.jmedchem.9b01743
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Lead Optimization and Avoidance of Reactive Metabolite Leading to PCO371, a Potent, Selective, and Orally Available Human Parathyroid Hormone Receptor 1 (hPTHR1) Agonist

Abstract: We have previously shown that the oral administration of the small molecule hPTHR1 agonist PCO371 and its lead compound, 1 (CH5447240) results in PTH-like calcemic and hypophostemic activity in thyroparathyroidectomized rats. However, 1 was converted to a reactive metabolite in a human liver microsome assay. In this article, we report on the modification path that led to an enhancement of PTHR1 agonistic activity and reduction in the formation of a reactive metabolite to result in a potent, selective, and oral… Show more

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Cited by 19 publications
(20 citation statements)
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References 16 publications
(26 reference statements)
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“…However, their studies were discontinued due to too weak affinities and efficacies. The third molecule (PCO371) is currently in phase 1 clinical trial as a potential orally available drug candidate for hypoparathyroidism treatment 34 . It is characterized as an orthosteric agonist of PTHR.…”
Section: Discussionmentioning
confidence: 99%
“…However, their studies were discontinued due to too weak affinities and efficacies. The third molecule (PCO371) is currently in phase 1 clinical trial as a potential orally available drug candidate for hypoparathyroidism treatment 34 . It is characterized as an orthosteric agonist of PTHR.…”
Section: Discussionmentioning
confidence: 99%
“…1 H NMR (CDCl 3 ) δ: 7.29 (1H, d, J = 7.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 7.15 (1H, d, J = 3.0 Hz), 7.05 (1H, t, J = 7.9 Hz), 6.54 (1H, d, J = 3.0 Hz), 4.16 (2H, t, J = 7.0 Hz), 3.64 (2H, t, J = 6.3 Hz), 1.97-1.89 (2H, m), 1.60-1.51 (2H, m), 1.26 (1H, brs). 13…”
Section: -(4-bromo-1h-indol-1-yl)butan-1-ol (7 H)mentioning
confidence: 99%
“…( 90 ) It increases serum calcium and decreases serum phosphorus in thyroparathyroidectomized rats. ( 91 ) This study has been terminated due to increases in liver enzymes in humans. (AAK, personal communication with Chugai).…”
Section: Emerging Therapies For Hypoptmentioning
confidence: 99%