Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

Didiuk, Mary T.; Griffith, David A.; Benbow, John W.; Liu, Kevin K.‐C.; Walker, Daniel P.; Bi, Fangchao; Morris, Joel; Guzmán-Pérez, Angel; Gao, Hua; Bechle, Bruce M.; Kelley, Ryan M.; Yang, Xiaojing; DiRico, Kenneth J.; Ahmed, Syed Mukhtar; Hungerford, William; DiBrinno, Joseph; Zawistoski, Michael P.; Bagley, Scott W.; Li, Jianke; Zeng, Yuan; Santucci, Stephanie; Oliver, Robert M.; Corbett, Matthew S.; Olson, Thanh V.; Chen, Chiliu; Li, Mei; Paralkar, Vishwas; Riccardi, Keith; Healy, David R.; Kalgutkar, Amit S.; Maurer, Tristan S.; Nguyen, HoangKim; Frederick, Kosea S.

doi:10.1016/j.bmcl.2009.07.004

Cited by 21 publications

(17 citation statements)

References 17 publications

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“…Further efforts to identify additional CaSR NAMs that may prove successful in treating osteoporosis led to the discovery of four chemically distinct NAM series exemplified by the quinazolinones ATF936 and AXT914 (Gerspacher et al, 2010), the pyridine Bristol Myers Squibb (BMS) compound 1 (Arey et al, 2005), a series of 3H-quinazoline-4-ones and 3H-pyrimidine-4-ones (Shcherbakova et al, 2005;Didiuk et al, 2009), and benzimidazoles (Gerspacher et al, 2010). A recent study o concentration (usually EC 80 or EC 20 , respectively).…”

Section: Ph Large Supraphysiological Changes In Buffer Ph Alter the mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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The calcium-sensing receptor (CaSR) is a class C G protein-coupled receptor that responds to multiple endogenous agonists and allosteric modulators, including divalent and trivalent cations, L-amino acids, g-glutamyl peptides, polyamines, polycationic peptides, and protons. The CaSR plays a critical role in extracellular calcium (Ca 2+ o) homeostasis, as demonstrated by the many naturally occurring mutations in the CaSR or its signaling partners that cause Ca 2+ o homeostasis disorders. However, CaSR tissue expression in mammals is broad and includes tissues unrelated to Ca 2+ o homeostasis, in which it, for example, regulates the secretion of digestive hormones, airway constriction, cardiovascular effects, cellular differentiation, and proliferation. Thus, although the CaSR is targeted clinically by the positive allosteric modulators (PAMs) cinacalcet, evocalcet, and etelcalcetide in hyperparathyroidism, it is also a putative therapeutic target in diabetes, asthma, cardiovascular disease, and cancer. The CaSR is somewhat unique in possessing multiple ligand binding sites, including at least five putative sites for the "orthosteric" agonist Ca 2+ o , an allosteric site for endogenous L-amino acids, two further allosteric sites for small molecules and the peptide PAM, etelcalcetide, and additional sites for other cations and anions. The CaSR is promiscuous in its G protein-coupling preferences, and signals via G q/11 , G i/o , potentially G 12/13 , and even G s in some cell types. Not surprisingly, the CaSR is subject to biased agonism, in which distinct ligands preferentially stimulate a subset of the CaSR's possible signaling responses, to the exclusion of others. The CaSR thus serves as a model receptor to study natural bias and allostery. Significance Statement-The calcium-sensing receptor (CaSR) is a complex G protein-coupled receptor that possesses multiple orthosteric and allosteric binding sites, is subject to biased signaling via several different G proteins, and has numerous (patho)physiological roles. Understanding the complexities of CaSR structure, function, and biology will aid future drug discovery efforts seeking to target this receptor for a diversity of diseases. This review summarizes what is known to date regarding key structural, pharmacological, and physiological features of the CaSR.

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Section: Ph Large Supraphysiological Changes In Buffer Ph Alter the mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

et al. 2020

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“…The quinazolinone series described above was used at Pfizer as a convenient starting point for a related series of pyrido[4,3-d]pyrimidinones (FiguRe 8) with optimized pharmacological and PK properties [57]. The ortho-trifluoromethyl residue at the pyridine ring of 15 proved ideal for potency, while the extent of the beneficial influence of the a-methyl group at the 3-phenethyl future science group substituent was highly dependent on the additional substitution pattern of the two phenyl rings.…”

Section: Quinazolin-4-ones and Analogsmentioning

confidence: 99%

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

Widler

2011

Future Med. Chem.

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The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium-sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone. Provided the effect of the calcilytic is of short duration, a bone anabolic effect should also result. Although the first calcilytic series became known approximately 10 years ago, the number of different structural types is still small today. This article outlines the quest from hits to potent development candidates of all relevant calcilytic series currently known. Even after the front-runners unexpectedly failed in the clinic, the approach for an oral alternative to parenteral PTH remains highly attractive.

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“…In this space, the high hepatic extraction provided additional challenges of requiring a higher degree of potency and the potential for a high degree of variability in the clinical pharmacokinetics. Ultimately, a series of 5-(trifluoromethyl)pyrido[4,3- d ]pyrimidin-4(3 H )-one derivatives were identified that met the design goals. − …”

Section: Approaches To Dose Predictionmentioning

confidence: 99%

Dose Predictions for Drug Design

Maurer

Smith²,

Beaumont

et al. 2020

J. Med. Chem.

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The efficacious dose of a drug is perhaps the most holistic metric reflecting its therapeutic potential. Dose is predicted at many stages in drug discovery and development. Prior to the 1990s, dose prediction was limited to the drug “working” at a reasonable dose and dose regimen in an animal model. Through the early 2000s, dose predictions were generated at candidate nomination and then refined during clinical development. Currently, dose predictions can be made early in drug discovery to enable drug design. Dose predictions at this stage can identify critical drug properties for a viable dose regimen and provide clinically relevant context to lead optimization. In this paper, we give an overview of the opportunities and challenges associated with dose prediction for drug design. A number of general considerations, approaches, and case examples are discussed.

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Short-acting 5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one derivatives as orally-active calcium-sensing receptor antagonists

Cited by 21 publications

References 17 publications

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

International Union of Basic and Clinical Pharmacology. CVIII. Calcium-Sensing Receptor Nomenclature, Pharmacology, and Function

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

Dose Predictions for Drug Design

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