Synthetic approaches to the 2014 new drugs.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of thirty-seven NCEs that were approved for the first time in 2014 and one drug which was approved in 2013 and was not covered in a previous edition of this review.

Synthetic approaches to the 2013 new drugs.

New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities (NCEs) provide insight into molecular recognition and also serve as leads for designing future new drugs. This annual review covers the synthesis of twenty-four NCEs that were approved for the first time in 2013 and two 2012 drugs which were not covered during the previous edition of this review.

Synthetic approaches to the 2012 new drugs.

New drugs introduced to the market every year represent a privileged structure for a particular biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of twenty-six NCEs that were launched or approved worldwide in 2012 and two additional drugs which were launched at the end of 2011.

Synthetic approaches to the 2011 new drugs.

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.

Conformationally-restricted cyclic sulfones as potent and selective mTOR kinase inhibitors.

Novel conformationally-restricted mTOR kinase inhibitors with cyclic sulfone scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the mTOR potency and selectivity against class I PI3Kα kinase. PF-05139962 was identified with excellent mTOR biochemical inhibition, cellular potency, kinase selectivity and in vitro ADME properties.

Synthetic approaches to the 2010 new drugs.

New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 15 NCEs that were launched anywhere in the world in 2010.

Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.

Intra-molecular hydrogen bonding was introduced to the quinazoline motif to form a pseudo ring (intra-molecular H-bond scaffold, iMHBS) to mimic our previous published core structures, pyrido[2.3-D]pyrimidin-7-one and pteridinone, as PI3K/mTOR dual inhibitors. This design results in potent PI3K/mTOR dual inhibitors and the purposed intra-molecular hydrogen bonding structure is well supported by co-crystal structure in PI3Kγ enzyme. In addition, a novel synthetic route was developed for these analogs.

Synthetic approaches to the 2009 new drugs.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 21 NCEs marketed in 2009.

Discovery tactics to mitigate toxicity risks due to reactive metabolite formation with 2-(2-hydroxyaryl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3h)-one derivatives, potent calcium-sensing receptor antagonists and clinical candidate(s) for the treatment of osteoporosis.

The synthesis and structure-activity relationship studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones as antagonists of the human calcium receptor (CaSR) have been recently disclosed [ Didiuk et al. ( 2009 ) Bioorg. Med. Chem. Lett. 19 , 4555 - 4559 ). On the basis of its pharmacology and disposition attributes, (R)-2-(2-hydroxyphenyl)-3-(1-phenylpropan-2-yl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3H)-one (1) was considered for rapid advancement to first-in-human (FIH) trials to mitigate uncertainty surrounding the pharmacokinetic/pharmacodynamic (PK/PD) predictions for a short-acting bone anabolic agent. During the course of metabolic profiling, however, glutathione (GSH) conjugates of 1 were detected in human liver microsomes in an NADPH-dependent fashion. Characterization of the GSH conjugate structures allowed insight(s) into the bioactivation pathway, which involved CYP3A4-mediated phenol ring oxidation to the catechol, followed by further oxidation to the electrophilic ortho-quinone species. While the reactive metabolite (RM) liability raised concerns around the likelihood of a potential toxicological outcome, a more immediate program goal was establishing confidence in human PK predictions in the FIH study. Furthermore, the availability of a clinical biomarker (serum parathyroid hormone) meant that PD could be assessed side by side with PK, an ideal scenario for a relatively unprecedented pharmacologic target. Consequently, progressing 1 into the clinic was given a high priority, provided the compound demonstrated an adequate safety profile to support FIH studies. Despite forming identical RMs in rat liver microsomes, no clinical or histopathological signs prototypical of target organ toxicity were observed with 1 in in vivo safety assessments in rats. Compound 1 was also devoid of metabolism-based mutagenicity in in vitro (e.g., Salmonella Ames) and in vivo assessments (micronuclei induction in bone marrow) in rats. Likewise, metabolism-based studies (e.g., evaluation of detoxicating routes of clearance and exhaustive PK/PD studies in animals to prospectively predict the likelihood of a low human efficacious dose) were also conducted, which mitigated the risks of idiosyncratic toxicity to a large degree. In parallel, medicinal chemistry efforts were initiated to identify additional compounds with a complementary range of human PK predictions, which would maximize the likelihood of achieving the desired PD effect in the clinic. The back-up strategy also incorporated an overarching goal of reducing/eliminating reactive metabolite formation observed with 1. Herein, the collective findings from our discovery efforts in the CaSR program, which include the incorporation of appropriate derisking steps when dealing with RM issues are summarized.

Design and synthesis of orally-active and selective azaindane 5HT2c agonist for the treatment of obesity.

Based on our original pyrazine hit, CP-0809101, novel conformationally-restricted 5HT2c receptor agonists with 2-piperazin-azaindane scaffold were designed. Synthesis and structure-activity relationship (SAR) studies are described with emphasis on optimization of the selectivity against 5HT2a and 5HT2b receptors with excellent 2c potency. Orally-active and selective compounds were identified with dose-responsive in vivo efficacy in our pre-clinical food intake model.

4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

Orally active and brain permeable proline amides as highly selective 5HT2c agonists for the treatment of obesity.

Brain-penetrable proline amides were developed as 5HT2c agonists with more than 1000-fold binding selectivity against 5HT2b receptor. After medicinal chemistry optimization and SAR studies, orally active proline amides with robust efficacy in a rodent food intake inhibition model were uncovered.

Direct photochemical cross-coupling between aliphatic acids and BF3K salts.

We describe a novel photoredox hetero-coupling reaction of two C (sp3) radicals from aliphatic acids or BF3K salts. The kinetic differences in radical persistence provide cross-selectivity, using an organic photoredox catalyst and an oxidant with visible light. This method exhibits broad scope, including several examples constructing sterically hindered C(sp3)-C(sp3) bonds.

Design and synthesis of pyridazinone-based 5-HT(2C) agonists.

The SAR of a series of pyridazinone derived 5-HT(2C) agonists has been explored and resulted in identification of a compound with excellent levels of 5-HT(2C) functional agonism and selectivity over 5-HT(2A) and 5-HT(2B). This compound displayed good in vivo efficacy in pre-clinical models of stress urinary incontinence, despite having physiochemical properties commensurate with impaired CNS penetration.

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

Synthesis and structure-activity relationship (SAR) studies on 5-trifluoromethylpyrido[4,3-d]pyrimidin-4(3H)-ones, a novel class of calcium receptor antagonists is described with particular emphasis on optimization of the pharmacokinetic/pharmacodynamic parameters required for a short duration of action compound. Orally-active compounds were identified which displayed the desired animal pharmacology (rapid and transient stimulation of parathyroid hormone) essential for bone anabolic effects.

Racemic N-methyl-4-[2-(methyl-sulfan-yl)-pyrimidin-4-yl]-1-(tetra-hydro-furan-3-yl)-1H-pyrazol-5-amine.

The title compound, C(13)H(17)N(5)OS, was obtained by cyclo-addition of 2-[2-(methyl-sulfan-yl)pyrimidin-4-yl]-3-oxo-propane-nitrile with (tetra-hydro-furan-3-yl)hydrazine dihydro-chloride and subsequent N-methyl-ation of 4-[2-(methyl-sulfan-yl)-pyrimidin-4-yl]-1-(tetra-hydro-furan-2-yl)-1H-pyrazol-5-amine with methyl iodide. The two mol-ecules in the asymmetric unit have opposite absolute configurations and are related by a noncrystallographic inversion center. Both feature intra-mol-ecular N-H⋯N hydrogen bonds. The geometry of the mol-ecules is similar to that observed in the structure of a single enanti-omer of the title compound.

(R)-N-Methyl-4-[2-(methyl-sulfan-yl)pyrimidin-4-yl]-1-(tetra-hydro-furan-3-yl)-1H-pyrazol-5-amine.

The chiral center at the substituted atom of the tetra-hydro-furanyl ring in the title compound, C(13)H(17)N(5)OS, has an R configuration. The methyl-sulfanylpyrimidine group and the pyrazole ring are almost coplanar [the maximum deviation from this plane is 0.070 (4) Å], the N-Me substituent being displaced from the methyl-sulfanylpyrimidine-pyrazole plane by 0.880 (4) Å. The secondary amine group participates in an intra-molecular hydrogen bond with the pyrimidine N atom in position 3.

(R)-4-[2-(Methyl-sulfanyl)pyrimidin-4-yl]-1-(tetra-hydro-furan-3-yl)-1H-pyrazol-5-amine.

The title compound, C(12)H(15)N(5)OS, was obtained by reaction of 2-(2-(methyl-thio)pyrimidin-4-yl)-3-oxopropane-nitrile with (tetra-hydro-furan-3-yl)hydrazine dihydro-chloride, and the racemic product was subsequently separated by chiral chromatography (first peak; [α](D) (20) = +51.3°). The chiral center at the substituted atom of the tetra-hydro-furanyl group has an R-configuration. The pyrimidine and pyrazolyl rings are almost coplanar, their mean planes forming a dihedral angle of 6.4 (1)°. One of the H atoms of the amino group participates in an intra-molecular hydrogen bond with the pyrimidine N atom in position 3. The second H atom is involved in an inter-molecular hydrogen bond, which links the mol-ecules into an infinite chain.

Synthetic approaches to the 2007 new drugs.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the syntheses of 19 NCEs marketed in 2007.

Synthetic approaches to the 2005 new drugs.

New drugs are introduced to the market every year and each individual drug represents a privileged structure for its biological target. In addition, these new chemical entities (NCEs) not only provide insights into molecular recognition, but also serve as drug-like leads for designing future new drugs. To these ends, this review covers the syntheses of 22 NCEs marketed in 2005.