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1.
ACS Med Chem Lett ; 8(9): 975-980, 2017 Sep 14.
Article in English | MEDLINE | ID: mdl-28947947

ABSTRACT

The predominant expression of phosphoinositide 3-kinase δ (PI3Kδ) in leukocytes and its critical role in B and T cell functions led to the hypothesis that selective inhibitors of this isoform would have potential as therapeutics for the treatment of allergic and inflammatory disease. Targeting specifically PI3Kδ should avoid potential side effects associated with the ubiquitously expressed PI3Kα and ß isoforms. We disclose how morphing the heterocyclic core of previously discovered 4,6-diaryl quinazolines to a significantly less lipophilic 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, followed by replacement of one of the phenyl groups with a pyrrolidine-3-amine, led to a compound series with an optimal on-target profile and good ADME properties. A final lipophilicity adjustment led to the discovery of CDZ173 (leniolisib), a potent PI3Kδ selective inhibitor with suitable properties and efficacy for clinical development as an anti-inflammatory therapeutic. In vitro, CDZ173 inhibits a large spectrum of immune cell functions, as demonstrated in B and T cells, neutrophils, monocytes, basophils, plasmocytoid dendritic cells, and mast cells. In vivo, CDZ173 inhibits B cell activation in rats and monkeys in a concentration- and time-dependent manner. After prophylactic or therapeutic dosing, CDZ173 potently inhibited antigen-specific antibody production and reduced disease symptoms in a rat collagen-induced arthritis model. Structurally, CDZ173 differs significantly from the first generation of PI3Kδ and PI3Kγδ-selective clinical compounds. Therefore, CDZ173 could differentiate by a more favorable safety profile. CDZ173 is currently in clinical studies in patients suffering from primary Sjögren's syndrome and in APDS/PASLI, a disease caused by gain-of-function mutations of PI3Kδ.

2.
Bioorg Med Chem Lett ; 25(22): 5121-6, 2015 Nov 15.
Article in English | MEDLINE | ID: mdl-26471092

ABSTRACT

A 1,2,4-triazole motif was employed as a bioisostere for the ester commonly used in muscarinic antagonists, and subsequent integrative conjugation to a ß2 agonist quinolinone furnished a new class of bifunctional MABAs for the treatment of COPD. Medicinal chemistry optimization using the principles of 'inhalation by design' furnished a clinical candidate with desirable pharmacological, pharmacokinetic and biopharmaceutical properties.


Subject(s)
Adrenergic beta-2 Receptor Agonists/chemical synthesis , Bronchodilator Agents/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Triazoles/chemical synthesis , Adrenergic beta-2 Receptor Agonists/pharmacokinetics , Adrenergic beta-2 Receptor Agonists/pharmacology , Animals , Biological Availability , Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacokinetics , Bronchodilator Agents/pharmacology , CHO Cells , Cricetulus , Dogs , Humans , Ipratropium/pharmacology , Muscarinic Antagonists/pharmacokinetics , Muscarinic Antagonists/pharmacology , Rats , Receptor, Muscarinic M3/antagonists & inhibitors , Salmeterol Xinafoate/pharmacology , Tiotropium Bromide/pharmacology , Triazoles/pharmacokinetics , Triazoles/pharmacology
3.
J Med Chem ; 54(19): 6888-904, 2011 Oct 13.
Article in English | MEDLINE | ID: mdl-21870878

ABSTRACT

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.


Subject(s)
Azetidines/chemical synthesis , Bronchodilator Agents/chemical synthesis , Diphenylacetic Acids/chemical synthesis , Pulmonary Disease, Chronic Obstructive/drug therapy , Receptor, Muscarinic M3/antagonists & inhibitors , Administration, Inhalation , Animals , Azetidines/chemistry , Azetidines/pharmacology , Bronchodilator Agents/chemistry , Bronchodilator Agents/pharmacology , CHO Cells , Cell Line , Cell Membrane Permeability , Cricetinae , Cricetulus , Diphenylacetic Acids/chemistry , Diphenylacetic Acids/pharmacology , Dogs , Female , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Kinetics , Male , Microsomes, Liver/metabolism , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/physiology , Radioligand Assay , Rats , Receptor, Muscarinic M3/metabolism , Recombinant Proteins/antagonists & inhibitors , Recombinant Proteins/metabolism , Stereoisomerism , Structure-Activity Relationship , Trachea/drug effects , Trachea/physiology
4.
Bioorg Med Chem Lett ; 21(11): 3404-6, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21515054

ABSTRACT

Heteroarylalanine derivatives 4 were designed as potential inhibitors of neutral endopeptidase (NEP EC 3.4.24.11). Selectivity over other zinc metalloproteinases was explored through occupation of the S2' subsite within NEP. Structural optimisation led to the identification of 5-phenyl oxazole 4f, a potent and selective NEP inhibitor. A crystal structure of the inhibitor bound complex is reported.


Subject(s)
Acids/chemical synthesis , Alanine/chemical synthesis , Neprilysin/antagonists & inhibitors , Oxazoles/chemistry , Oxazoles/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Acids/chemistry , Acids/pharmacology , Alanine/chemistry , Alanine/pharmacology , Crystallography, X-Ray , Enzyme Activation/drug effects , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protease Inhibitors/chemistry
5.
Bioorg Med Chem Lett ; 20(1): 92-6, 2010 Jan 01.
Article in English | MEDLINE | ID: mdl-19954973

ABSTRACT

A suitable inhibitor of activated thrombin activatable fibrinolysis inhibitor (TAFIa) has the potential to be a novel treatment for thrombosis. The TAFIa inhibitor UK-396082 (1) was used as a starting point to seek more potent analogues. With knowledge of encouraging human pharmacokinetics and toleration for the clinical candidate (1), the programme continued to seek structure-activity relationships (SAR) that could positively impact on both potency and half-life, and therefore the projected dose of any future nominated clinical agent. A series of oxygenated analogues based on compound 1 were prepared to evaluate changes in pharmacology, selectivity and pharmacokinetics.


Subject(s)
Amino Acids/chemistry , Carboxypeptidase B2/antagonists & inhibitors , Fibrinolytic Agents/chemistry , Imidazoles/chemistry , Oxygen/chemistry , Protease Inhibitors/chemistry , Administration, Oral , Amino Acids/chemical synthesis , Amino Acids/pharmacokinetics , Animals , Carboxypeptidase B2/metabolism , Fibrinolytic Agents/chemical synthesis , Fibrinolytic Agents/pharmacokinetics , Half-Life , Humans , Imidazoles/chemical synthesis , Imidazoles/pharmacokinetics , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Rats , Structure-Activity Relationship
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