The Discovery of a Dual TTK Protein Kinase/CDC2-Like Kinase (CLK2) Inhibitor for the Treatment of Triple Negative Breast Cancer Initiated from a Phenotypic Screen.

Triple negative breast cancer (TNBC) remains a serious unmet medical need with discouragingly high relapse rates. We report here the synthesis and structure-activity relationship (SAR) of a novel series of 2,4,5-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines with potent activity against TNBC tumor cell lines. These compounds were discovered from a TNBC phenotypic screen and possess a unique dual inhibition profile targeting TTK (mitotic exit) and CLK2 (mRNA splicing). Design and optimization, driven with a TNBC tumor cell assay, identified potent and selective compounds with favorable in vitro and in vivo activity profiles and good iv PK properties. This cell-based driven SAR produced compounds with strong single agent in vivo efficacy in multiple TNBC xenograft models without significant body weight loss. These data supported the nomination of CC-671 into IND-enabling studies as a single agent TNBC therapy.

Rules and stereoelectronic guidelines for the anionic nucleophilic displacement of furanoside and furanose O-sulfonates.

Rules for predicting anionic SN2 displacement viability in furanose and furanoside sulfonates are presented.

An update of the rules for pyranoside sulfonate displacement.

The original 1967 Richardson-Hough rules for predicting SN2 displacement viability in carbohydrate sulfonate derivatives with external nucleophiles have now been updated. Not only do the original rules still hold, but the newly updated rules rationalize why O-triflates (trifluoromethanesulfonate esters) frequently allow many seemingly "disallowed" pyranosidic nucleophilic substitutions to proceed. The new guidelines, which are based on three decades of experimental evidence, allow the feasibility of many pyranosidic O-triflate SN2 displacements to be gauged beforehand.

Proposing advancement criteria for efficient DMPK triage of new chemical entities.

With the goal of refining our discovery DMPK workflow, we conducted a retrospective analysis on internal Celgene compounds by calculating the physicochemical properties and gathering data from several assays including solubility, rat and human liver S9 stability, Caco-2 permeability, and rat intravenous (iv.) and oral pharmacokinetics. Our analysis identified plasma clearance to be most statistically relevant for prediction of oral exposure. In rat, compounds with rat S9 stability of ≥70% at 60 min and a plasma clearance of ≤43 ml/min/kg had the greatest chance of achieving oral exposures above 3 µM.h. Compounds with the dual advantage of plasma clearance ≤43 ml/min/kg and Caco-2 permeability ≥8 × 10(-6) cm/s or efflux ratio ≤8 were highly likely to achieve those oral exposures. Implementation of these criteria leads to a significant increase in efficiency, good pharmacokinetic properties, cost savings and a reduction in the use of animals.

Lead Diversification 2: application to P38, gMTP and lead compounds.

Lead Diversification is a new technology platform developed at Pfizer for the functionalization of drug molecules using C-H activation. We describe its application to some drug programs such as P38 and gMTP and the development of some new plate based screens including a fluorination screen.

Discovery of a selective small-molecule melanocortin-4 receptor agonist with efficacy in a pilot study of sexual dysfunction in humans.

The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.

Triazole oxytocin antagonists: Identification of an aryloxyazetidine replacement for a biaryl substituent.

A series of aryloxyazetidines, aryloxypyrrolidines and aryloxypiperidines were designed based on structural overlap with previously reported arylpyrazine Oxytocin antagonists. Similarly high levels of Oxytocin antagonism were achievable in these new series. Several aryloxyazetidines also showed high levels of selectivity, with one compound, 25, displaying promising in vivo pharmacokinetics and significantly improved aqueous solubility over related compounds containing a biaryl substituent.

Optimising metabolic stability in lipophilic chemical space: the identification of a metabolically stable pyrazolopyrimidine CRF-1 receptor antagonist.

Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group.

Triazole oxytocin antagonists: identification of aryl ether replacements for a biaryl substituent.

Several potent aryl ether/triazole oxytocin antagonists are described. The lead compound in this series had significantly improved aqueous solubility over related systems containing a biaryl substituent.