Defining patient centricity with patients for patients and caregivers: a collaborative endeavour.

Background: Patient engagement is an essential aspect in the research/development of biopharmaceutical products and disease management. Improving the lives of patients requires a deep understanding of their medical conditions, experiences, needs and priorities. However, a consistent definition of patient centricity is lacking.

Culture and Process Change as a Priority for Patient Engagement in Medicines Development.

Patient Focused Medicines Development (PFMD) is a not-for-profit independent multinational coalition of patients, patient stakeholders, and the pharmaceutical industry with interests across diverse disease areas and conditions. PFMD aims to facilitate an integrated approach to medicines development with all stakeholders involved early in the development process. A key strength of the coalition that differentiates it from other groups that involve patients or patient groups is that PFMD has patient organizations as founding members, ensuring that the patient perspective is the starting point when identifying priorities and developing solutions to meet patients' needs.

Diastereoselective synthesis of fused lactone-pyrrolidinones; application to a formal synthesis of (-)-salinosporamide A.

A mild, diastereoselective synthesis of fused lactone-pyrrolidinones using an oxidative radical cyclization is reported. The methodology is demonstrated in a formal synthesis of (-)-salinosporamide A.

The identification of novel orally active mGluR5 antagonist GSK2210875.

The identification of novel orally active mGluR5 antagonist GSK2210875 is described.

Novel N-Substituted Benzimidazolones as Potent, Selective, CNS-Penetrant, and Orally Active M1 mAChR Agonists.

Virtual screening of the corporate compound collection yielded compound 1 as a subtype selective muscarinic M1 receptor agonist hit. Initial optimization of the N-capping group of the central piperidine ring resulted in compounds 2 and 3 with significantly improved potency and selectivity. Subsequent optimization of substituents on the phenyl ring of the benzimidazolone moiety led to the discovery of novel muscarinic M1 receptor agonists 4 and 5 with excellent potency, general and subtype selectivity, and pharmacokinetic (PK) properties including good central nervous system (CNS) penetration and oral bioavailability.

The discovery of a series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles as highly brain penetrant, selective muscarinic M1 agonists.

A series of N-substituted 3-(4-piperidinyl)-1,3-benzoxazolinones and oxindoles are reported which were found to be potent and selective muscarinic M1 agonists. By control of the physicochemical characteristics of the series, particularly the lipophilicity, compounds with good metabolic stability and excellent brain penetration were identified. An exemplar of the series was shown to be pro-cognitive in the novel object recognition rat model of temporal induced memory deficit.

2' biaryl amides as novel and subtype selective M1 agonists. Part I: Identification, synthesis, and initial SAR.

Biaryl amides were discovered as novel and subtype selective M(1) muscarinic acetylcholine receptor agonists. The identification, synthesis, and initial structure-activity relationships that led to compounds 3j and 4c, possessing good M(1) agonist potency and intrinsic activity, and subtype selectivity for M(1) over M(2-5), are described.

2' biaryl amides as novel and subtype selective M1 agonists. Part II: Further optimization and profiling.

Further optimization of the biaryl amide series via extensively exploring structure-activity relationships resulted in potent and subtype selective M(1) agonists exemplified by compounds 9a and 9j with good rat PK properties including CNS penetration. Synthesis, structure-activity relationships, subtype selectivity for M(1) over M(2-5), and DMPK properties of these novel compounds are described.