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1.
J Med Chem ; 65(20): 13629-13644, 2022 10 27.
Article in English | MEDLINE | ID: mdl-36251573

ABSTRACT

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.


Subject(s)
Angioedemas, Hereditary , Humans , Administration, Oral , Angioedemas, Hereditary/drug therapy , Angioedemas, Hereditary/metabolism , Antiviral Agents/therapeutic use , Aspartic Acid , Bradykinin/metabolism , Plasma Kallikrein
2.
J Med Chem ; 51(24): 8124-34, 2008 Dec 25.
Article in English | MEDLINE | ID: mdl-19053774

ABSTRACT

Vasopressin (AVP) is a hormone that stimulates an increase in water permeability through activation of V2 receptors in the kidney. The analogue of AVP, desmopressin, has proven an effective drug for diseases where a reduction of urine output is desired. However, its peptidic nature limits its bioavailability. We report herein the discovery of potent, nonpeptidic, benzylurea derived agonists of the vasopressin V2 receptor. We describe substitutions on the benzyl group to give improvements in potency and subsequent modifications to the urea end group to provide improvements in solubility and increased oral efficacy in a rat model of diuresis. The lead compound 20e (VA106483) is reported for the first time and has been selected for clinical development.


Subject(s)
Chemistry, Pharmaceutical/methods , Receptors, Vasopressin/agonists , Urea/chemistry , Administration, Oral , Animals , Caco-2 Cells , Diuresis , Dose-Response Relationship, Drug , Drug Design , Drug Evaluation, Preclinical , Humans , Models, Chemical , Rats , Rats, Brattleboro , Solubility
3.
Bioorg Med Chem Lett ; 14(17): 4585-9, 2004 Sep 06.
Article in English | MEDLINE | ID: mdl-15357997

ABSTRACT

A library of compounds targeted to the vasopressin/oxytocin family of receptors was screened for activity at a cloned human oxytocin receptor using a reporter gene assay. Potency and selectivity were optimised to afford compound 39, EC50 = 33 nM. This series of compounds represents the first disclosed, non-peptide, low molecular weight agonists of the hormone oxytocin (OT).


Subject(s)
Benzazepines/chemistry , Oxytocin/agonists , Pyrrolidines/chemistry , Angiotensin Receptor Antagonists , Animals , Antidiuretic Hormone Receptor Antagonists , Benzazepines/metabolism , CHO Cells , Cell Line , Cricetinae , Dose-Response Relationship, Drug , Humans , Oxytocin/antagonists & inhibitors , Oxytocin/metabolism , Pyrrolidines/metabolism , Receptors, Angiotensin/agonists , Receptors, Angiotensin/metabolism , Receptors, Oxytocin/agonists , Receptors, Oxytocin/antagonists & inhibitors , Receptors, Oxytocin/metabolism , Receptors, Vasopressin/agonists , Receptors, Vasopressin/metabolism
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