Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • Because of the commercial availability of some acetamide phe

    2021-12-01

    Because of the commercial availability of some acetamide phenol starting materials, a few acetamide final products (such as and , ) were directly synthesized via a Mitsunobu reaction with chloropyrimidine piperidinyl cyclopropyl alcohol . The 3-pyridinyl analogue was synthesized by a nucleophilic aromatic substitution reaction between chloropyridinyl azetidine acetamide and chloropyrimidine piperidinyl cyclopropyl alcohol . Another alternative synthesis was described in . Readily available bromo phenol was coupled with MOM pyrimidine piperidinyl cyclopropyl alcohol via a Mitsunobu reaction. Then a Negishi reaction of bromide with (2-(-butoxy)-2-oxoethyl)zinc(II) bromide followed by -butyl ester deprotection gave the MOM pyrimidine phenylacetic Cell Cycle Compound Library . The final product was synthesized by a routine HATU amide coupling reaction. SAR and SPR results of acetamides synthesized in , are summarized in . Our previous preclinical candidate is also shown for comparison. We were pleased to find that secondary amide had excellent GPR119 potency (hGPR119 EC=1.8nM). However, its FaSSIF solubility (22μM) remained as poor as that of compound (21μM). In addition to , other secondary amides we synthesized all exhibited poor FaSSIF solubility. Primary amide () had reduced GPR119 potency. In contrast to primary amide and secondary amide , tertiary amide had improved FaSSIF solubility (97μM) and maintained excellent GPR119 potency (hGPR119 EC=0.8nM). Furthermore we were pleased to find that in rat PK studies, t of tertiary amide became 4.7h compared to a very long t (15h) of compound . The 3-pyridinyl acetamide () which has a pyridine moiety as compound , was less active than phenyl . 3-F substituted () was also less active (hGPR119 EC=2.2nM) than . However, 2-F substituted was more potent (hGPR119 EC=0.2nM) than unsubstituted (hGPR119 EC=0.8nM). Compound also had good FaSSIF solubility (137μM). SAR studies from an amide library synthesis revealed that while a variety of amines were tolerated for GPR119 potency, azetidine amide was one of the most potent analogues (for example, compared with hydroxyl azetidine and piperidine amide ). However with a long projected human half-life (∼46h based on allometric scaling from rat), compound was still not ideally matched for a QD fixed-dose combination (FDC) partner with sitagliptin. Although hydroxyl azetidine had a reduced rat t (3.5h), its hERG activity (hERG IC=5.3μM) remained a concern. Chloropyrimidine compounds – all had moderate hERG inhibition. Many historical GPR119 agonists have struggled with hERG inhibition as well as solubility issues, and some even had CNS side effects, potentially due to off-target activities that accompany their highly lipophilicic features., We next turned our attention to piperidine capping groups on the right-hand side (RHS) of the molecule such as ethylpyrimidine, oxadiazole and carbamates which are structure moieties of some clinical GPR119 agonists. Ethylpyrimidine maintained excellent potency (hGPR119 EC=0.4nM), however, with no improvement in hERG selectivity. Methylcyclopropyl carbamate was less active in an IKr binding assay (hERG IC=23μM), however, it was also less potent at GPR119 (hGPR119 EC=3.3nM). Moreover, in a cardiac ion channel blockade activity assay, functional hERG inhibition for was determined to be more potent (hERG IC=8.6μM) than in IKr binding assay. Isopropyl oxadiazole () also reduced potency (hGPR119 EC=2.0nM) relative to the chloropyrimidine , and hERG selectivity was still suboptimal (hERG IC=7.0μM). Furthermore, the projected human half-lifes of several isopropyl oxadiazole phenylacetamides including were generally projected to be too short to support a QD human dose less than 200mg. We previously reported that a MOM pyrimidine improved solubility in the benzyloxy series relative to the corresponding chloropyrimidine RHS moiety. We were pleased to discover that the corresponding MOM pyrimidine compound not only had excellent FaSSIF solubility (152μM) and GPR119 potency (hGPR119 EC=0.7nM), but also reduced hERG activity (hERG IC=19μM). Since 2-F substitution improved GPR119 potency (compound vs ), the 2,6-difluoro analogue was synthesized. Compound now had hGPR119 EC=0.2nM. In IKr binding assay, its hERG IC=9.2μM. In cardiac ion channel blockade activity assay, functional hERG inhibition was confirmed to be mild (hERG IC=12μM). Compound also had a favorable rat t (3.5h).