1. 原文标题及出处：
Structure-based design and optimization of potent inhibitors of the adenoviral protease
Bioorganic & Medicinal Chemistry Letters 25 (2015) 438–443
doi:10.1016/j.bmcl.2014.12.057
公司/组织：诺华
候选药物化学结构式/活性：
靶点/作用机制：腺病毒蛋白酶抑制剂
摘要原文：
Adenoviral infections are associated with a wide range of acute diseases, among which ocular viral conjunctivitis (EKC) and disseminated disease in immunocompromised patients. To date, no approved specific anti-adenoviral drug is available, but there is a growing need for an effective treatment of such infections. The adenoviral protease, adenain, plays a crucial role for the viral lifecycle and thus represents an attractive therapeutic target. Structure-guided design with the objective to depeptidize tetrapeptide nitrile 1 led to the novel chemotype 2. Optimization of scaffold 2 resulted in picomolar adenain inhibitors 3a and 3b. In addition, a complementary series of irreversible vinyl sulfone containing inhibitors were rationally designed, prepared and evaluated against adenoviral protease. High resolution X-ray co-crystal structures of representatives of each series proves the successful design of these inhibitors and provides an excellent basis for future medicinal chemistry optimization of these compounds.
备注：
腺病毒是双链DNA病毒，与多种急性、高感染性疾病相关，比如胃肠道疾病、流行性角膜结膜炎等。
2. 原文标题及出处：
Discovery of piperidine ethers as selective orexin receptor antagonists (SORAs) inspired by filorexant
Bioorganic & Medicinal Chemistry Letters 25 (2015) 444–450
doi:10.1016/j.bmcl.2014.12.056
公司/组织：默克
候选药物化学结构式/活性：
靶点/作用机制：食欲素受体拮抗剂
摘要原文：
Highly selective orexin receptor antagonists (SORAs) of the orexin 2 receptor (OX2R) have become attractive targets both as potential therapeutics for insomnia as well as biological tools to help further elucidate the underlying pharmacology of the orexin signaling pathway. Herein, we describe the discovery of a novel piperidine ether 2-SORA class identified by systematic lead optimization beginning with filorexant, a dual orexin receptor antagonist (DORA) that recently completed Phase 2 clinical trials. Changes to the ether linkage and pendant heterocycle of filorexant were found to impart significant selectivity for OX2R, culminating in lead compound PE-6. PE-6 displays sub-nanomolar binding affinity and functional potency on OX2R while maintaining >1600-fold binding selectivity and >200-fold functional selectivity versus the orexin 1 receptor (OX1R). PE-6 bears a clean off-target profile, a good overall preclinical pharmacokinetic (PK) profile, and reduces wakefulness with increased NREM and REM sleep when evaluated in vivo in a rat sleep study. Importantly, subtle structural changes to the piperidine ether class impart dramatic changes in receptor selectivity. To this end, our laboratories have identified multiple piperidine ether 2-SORAs, 1-SORAs, and DORAs, providing access to a number of important biological tool compounds from a single structural class.
备注：
Suvorexant和filorexant 是默克研发的双食欲素受体拮抗剂，正在进行临床试验； suvorexant (Belsomra) 是通过FDA批准的第一个食欲素受体拮抗剂用于治疗失眠。
3. 原文标题及出处：
Structure-based design of low-nanomolar PIM kinase inhibitors
Bioorganic & Medicinal Chemistry Letters 25 (2015) 474–480
doi:10.1016/j.bmcl.2014.12.041
公司/组织：Biogen Idec
候选药物化学结构式/活性：
靶点/作用机制：PIM激酶抑制剂
摘要原文：
PIM kinases are implicated in variety of cancers by promoting cell survival and proliferation and are targets of interest for therapeutic intervention. We have identified a low-nanomolar pan-PIM inhibitor (PIM1/2/3 potency 5:14:2 nM) using structure based modeling. The crystal structure of this compound with PIM1 confirmed the predicted binding mode and protein–ligand interactions except those in the acidic ribose pocket. We show the SAR suggesting the importance of having a hydrogen bond donor in this pocket for inhibiting PIM2; however, this interaction is not important for inhibiting PIM1 or PIM3. In addition, we report the discovery of a new class of PIM inhibitors by using computational de novo design tool implemented in MOE software (Chemical Computing Group). These inhibitors have a different interaction profile.
备注：
4. 原文标题及出处：
Identification of nicotinamide phosphoribosyltransferase (NAMPT) inhibitors with no evidence of CYP3A4 time-dependent inhibition and improved aqueous solubility
Bioorganic & Medicinal Chemistry Letters 25 (2015) 529–541
doi:10.1016/j.bmcl.2014.12.026
公司/组织：Genentech
候选药物化学结构式/活性：
靶点/作用机制：烟酰胺磷酸核糖基转移酶（NAMPT）抑制剂
摘要原文：
Herein we report the optimization efforts to ameliorate the potent CYP3A4 time-dependent inhibition (TDI) and low aqueous solubility exhibited by a previously identified lead compound from our NAMPT inhibitor program (1, GNE-617). Metabolite identification studies pinpointed the imidazopyridine moiety present in 1 as the likely source of the TDI signal, and replacement with other bicyclic systems was found to reduce or eliminate the TDI finding. A strategy of reducing the number of aromatic rings and/or lowering c Log D7.4 was then employed to significantly improve aqueous solubility. These efforts culminated in the discovery of 42, a compound with no evidence of TDI, improved aqueous solubility, and robust efficacy in tumor xenograft studies.
备注：
通过抑制NAMPT 阻断NAM-NAD循环通路可能是一个治疗癌症的有效策略。
5. 原文标题及出处：
Selective CB2 receptor agonists. Part 1: The identification of novel ligands through computer-aided drug design (CADD) approaches
Bioorganic & Medicinal Chemistry Letters 25 (2015) 575–580
doi:10.1016/j.bmcl.2014.12.033
公司/组织：Boehringer Ingelheim
候选药物化学结构式/活性：
靶点/作用机制：大麻素受体2（CB2）激动剂
摘要原文：
Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.
备注：
CB2与免疫调节功能相关。CB2小分子调节剂与肿瘤、免疫、神经疼痛、多发性硬化症以及神经退行性疾病相关。
6. 原文标题及出处：
Selective CB2 receptor agonists. Part 2: Structure–activity relationship studies and optimization of proline-based compounds
Bioorganic & Medicinal Chemistry Letters 25 (2015) 581–586
doi:10.1016/j.bmcl.2014.12.019
公司/组织：Boehringer Ingelheim
候选药物化学结构式/活性：
靶点/作用机制：CB2激动剂
摘要原文：
Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure–activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.
备注：
7. 原文标题及出处：
Selective CB2 receptor agonists. Part 3: The optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model
Bioorganic & Medicinal Chemistry Letters 25 (2015) 587–592
doi:10.1016/j.bmcl.2014.12.031
公司/组织：Boehringer Ingelheim
候选药物化学结构式/活性：
靶点/作用机制：CB2激动剂
摘要原文：
A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g., 30) that displayed selectivity over cannabinoid receptor 1 (CB1) and acceptable drug like properties. In rats, compound 30 demonstrated a favorable pharmacokinetic profile and efficacy in a Streptozotocin-induced diabetic neuropathy model, with full reversal of mechanical hyperalgesia.
备注：
8. 原文标题及出处：
A selective small molecule NOP (ORL-1 receptor) partial agonist for the treatment of anxiety
Bioorganic & Medicinal Chemistry Letters 25 (2015) 602–606
doi:10.1016/j.bmcl.2014.12.015
公司/组织：杨森
候选药物化学结构式/活性：
靶点/作用机制：阿片样受体1 （ORL-1）部分激动剂
摘要原文：
Small molecule (1) has been identified as a selective partial agonist of Opioid Receptor Like-1 (ORL-1) with potential utility for the treatment of anxiety and other disorders. Nociceptin (orphanin FQ) is an endogenous peptide ligand that binds to ORL-1, however it does not bind the classical δ, μ and κ opioid receptors with high affinity. The synthesis of 1 involved using a molecular diversity approach, to rapidly advance a library of compounds for biological testing. A lead selective potent partial agonist (35-fold ORL-1/Mu) progressed to ORL-1 (NOP or OP4) proof of concept testing in advanced studies. The synthetic approach and biological data for the related chemical series will be presented.
备注：
ORL-1激动剂可用作非典型阿片止痛药和减缓由脊髓、周围神经受伤或炎症引起的疼痛。
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